Novel and specific inhibitors of cytochrome p450 26 retinoic acid hydroxylase

ABSTRACT

The present disclosure is generally directed to compositions and methods for treating diseases that are ameliorated by the inhibition of CYP26 mediated retinoic acid metabolism. The compositions comprise compounds of formula (I). A repreid50000060307390 IB/345 nullsents aryl optionally substituted with one, two, three, or four groups that are each independently halogen, cyano, nitro, C 1-6  alkyl, C 1-6  haloalkyl, —NH 2 , —NH(C 1 -C 6  alkyl), —N(C 1 -C 6  alkyl) 2 , —OH, C 1 -C 6  alkoxy, and C 1 -C 6  haloalkoxy; X is a bond, —CH 2 —, —CHR 5 —, —C═CHR 4 —, —NR 4 —, —N═O—R 4 —, —O—, —S—, —SO—, —SO 2 —, —C(O)—, or —C(NR 4 )—, or X is of formula (a), (b) or (c), wherein each n is independently 1, 2, or 3; each R 4  is independently hydrogen or C 1-6  alkyl; R 5  is independently hydrogen, C 1-6  alkyl, or —OR 6 , where R 6  is selected from the group consisting of hydrogen, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyL C 3-12  cycloalkyl, heterocyclyl, aryl, arylC 1-6  alkyl, heteroaryl, or heteroarylC 1-6  alkyl; Y is C 1-6  alkylene, C 2-6  alkenylene, or C 2-6  alkylylene moiety.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of the filing dates of U.S.Provisional Patent Application Ser. No. 61/867,892, filed Aug. 20, 2013,which is hereby incorporated by reference in its entirety.

STATEMENT OF GOVERNMENT SUPPORT

This invention was made with government support under R01GM081569awarded by the National Institutes of Health (NIH), under UL1 TR000423National Center for Advancing Translational Sciences at the NationalInstitutes of Health (NIH), and under R41AG046987 awarded by theNational Institute on Aging and under P30NS055022 awarded by theNational Institute of Neurological Disorders and Stroke. The governmenthas certain rights in the invention.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present disclosure is generally directed to compositions and methodsfor treating diseases that are ameliorated by the inhibition of CYP26mediated retinoic acid metabolism.

2. Description of Related Art

Retinoic acid (RA), the active metabolite of vitamin A, is an importantendogenous signaling molecule regulating cell cycle and maintenance ofepithelia. RA isomers are also used as drugs to treat various cancersand dermatological diseases. However, the therapeutic uses of RA isomersare limited due to side effects such as teratogenicity and resistance totreatment, emerging mainly from autoinduction of RA metabolism. Toimprove the therapeutic usefulness of retinoids, RA metabolism blockingagents (RAMBAs) have been developed. These inhibitors generally targetthe cytochrome P450 (CYP) enzymes because RA clearance is predominantlymediated by P450s. Since the initial identification of inhibitors of RAmetabolism, CYP26 enzymes have been characterized as the main enzymesresponsible for RA clearance.

The CYP26A1 and CYP26B1 enzymes appear to be the predominantall-trans-retinoic acid (atRA) hydroxylases in humans, both in the liverand in extrahepatic tissues. In cell culture, differential expression ofCYP26A1 changes the cells susceptibility to apoptosis, presumably viadifferent metabolic capacity of the cells. Similarly, inhibition of P450mediated atRA metabolism makes the cells more susceptible toproapoptotic effects of atRA. In acute promyelocytic leukemia patientsreceiving atRA therapy, therapy resistance and relapse has beenattributed to CYP26 induction and increased atRA elimination in cancercells. Whether any of the known CYP26A1 inhibitors also inhibit CYP26B1is currently unknown and the pharmacological effects of selectiveCYP26A1 versus CYP26B1 inhibition have not been characterized.

SUMMARY OF THE INVENTION

The basic principle of development of CYP26 inhibitors is thatendogenous RA concentrations will be increased in the presence of aCYP26 inhibitor, thus, potentiating the activity of endogenous RA incell-type specific manner. This will reduce side effects compared toadministration of RA and allow for more targeted therapy. In clinicaltrials, inhibitors of RA metabolism have been effective in treatment ofacne and psoriasis and other dermatological conditions as well as insome cancers, such as acute promyelocytic leukemia (APL). But, no CYP26inhibitor has yet been approved for clinical use. The present disclosureprovides new and effective inhibitors of CYP26.

Thus, one aspect of the disclosure provides compounds of formula (I):

or a pharmaceutically acceptable salt thereof, wherein

-   A represents aryl optionally substituted with one, two, three, or    four groups that are each independently halogen, cyano, nitro, C₁₋₆    alkyl, C₁₋₆ haloalkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂,    —OH, C₁-C₆ alkoxy, and C₁-C₆ haloalkoxy;-   X is a bond, —CH₂—, —CHR⁵—, —C═CHR⁴—, —NR⁴—, —N═O—R⁴—, —O—, —S—,    —SO—, —SO₂—, —C(O)—, or —C(NR⁴)—, or X is of formula

wherein

-   -   each n is independently 1, 2, or 3;    -   each R⁴ is independently hydrogen or C₁₋₆ alkyl;    -   R⁵ is independently hydrogen, C₁₋₆ alkyl, or —OR⁶, where R⁶ is        selected from the group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₃₋₁₂ cycloalkyl, heterocyclyl, aryl,        arylC₁₋₆ alkyl, heteroaryl, or heteroarylC₁₋₆ alkyl;

-   Y is C₁₋₆ alkylene, C₂₋₆ alkenylene, or C₂₋₆ alkylylene moiety;

-   R¹ is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ haloalkyl, C₃₋₁₂ cycloalkyl,    heterocyclyl, aryl, arylC₁₋₆ alkyl, heteroaryl, or heteroarylC₁₋₆    alkyl, wherein the alkyl, aryl, arylalkyl, heteroaryl, and    heteroarylalkyl are optionally substituted with one, two, three, or    four groups that are each independently halogen, cyano, nitro, C₁₋₆    alkyl, C₁₋₆ haloalkyl, —OR⁷, —SR⁷, —N(R⁷)₂, —C(O)R⁷, —C(O)OR⁷,    —C(O)N(R⁷)₂, —S(O)₂R⁷, —OC(O)R⁷, —OC(O)OR⁷, —OC(O)N(R⁷)₂,    —N(R⁷)C(O)R⁷, —N(R⁷)C(O)OR⁷, or —N(R⁷)C(O)N(R⁷)₂, wherein each R⁷ is    independently hydrogen or C₁₋₆ alkyl;

-   R² is hydrogen, halogen, C₁₋₆ alkyl, or —OR⁸, where R⁸ is selected    from the group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl,    C₂₋₆ alkynyl, C₃₋₁₂ cycloalkyl, heterocyclyl, aryl, arylC₁₋₆ alkyl,    heteroaryl, or heteroarylC₁₋₆ alkyl, wherein the alkyl, aryl,    arylalkyl, heteroaryl, and heteroarylalkyl are optionally    substituted with one, two, three, or four groups that are each    independently halogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl,    —OR⁷, —SR⁷, —N(R⁷)₂, —C(O)R⁷, —C(O)OR⁷, —C(O)N(R⁷)₂, —S(O)₂R⁷,    —OC(O)R⁷, —OC(O)OR⁷, —OC(O)N(R⁷)₂, —N(R⁷)C(O)R⁷, —N(R⁷)C(O)OR⁷, or    —N(R⁷)C(O)N(R⁷)₂, wherein each R⁷ is independently hydrogen or C₁₋₆    alkyl;

-   or R¹ and R² together with the atoms to which they are attached form    a C₃₋₁₂ cycloalkyl, heterocyclyl, aryl, or heteroaryl, each    optionally substituted with one, two, three, or four groups that are    each independently halogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆    haloalkyl, —OR⁷, —SR⁷, —N(R⁷)₂, —C(O)R⁷, —C(O)OR⁷, —C(O)N(R⁷)₂,    —S(O)₂R⁷, —OC(O)R⁷, —OC(O)OR⁷, —OC(O)N(R⁷)₂, —N(R⁷)C(O)R⁷,    —N(R⁷)C(O)OR⁷, or —N(R⁷)C(O)N(R⁷)₂; and

-   R³ is hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —OR, —SR, or —NR₂,    -   and each R is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl,        C₁₋₆ haloalkyl, C₃₋₁₂ cycloalkyl, heterocyclyl, aryl, arylC₁₋₆        alkyl, heteroaryl, or heteroarylC₁₋₆ alkyl, wherein the alkyl,        aryl, arylalkyl, heteroaryl, and heteroarylalkyl are optionally        substituted with one, two, three, or four groups that are each        independently halogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl,        —OR⁰, —SR⁰, —N(R⁰)₂, —C(O)R⁰, —C(O)OR⁰, —C(O)N(R⁰)₂, —S(O)₂R⁰,        —OC(O)R⁰, —OC(O)OR⁰, —OC(O)N(R⁰)₂, —N(R⁰)C(O)R⁰, —N(R⁰)C(O)OR⁰,        or —N(R⁰)C(O)N(R⁰)₂, wherein each R⁰ is independently hydrogen        or C₁₋₆ alkyl.

In another aspect, the disclosure provides pharmaceutical compositionscomprising one or more of compounds of the disclosure and apharmaceutically acceptable carrier, diluent, or excipient.

In another aspect, the disclosure provides methods for treating diseasesthat are ameliorated by the inhibition of CYP26 mediated retinoic acidmetabolism comprising providing to a patient in need of such treatment atherapeutically effective amount of either (a) one or more of compoundsof formula (I), or (b) a pharmaceutical composition comprising one ormore of compounds of formula (I) and a pharmaceutically acceptableexcipient, carrier, or diluent.

In another aspect, the disclosure provides methods for treating diseasesthat are ameliorated by the inhibition of CYP26 mediated retinoic acidmetabolism comprising providing to a patient in need of such treatment atherapeutically effective amount of either (a) one or more of compoundsof formula (II), or (b) a pharmaceutical composition comprising one ormore of compounds of formula (II) and a pharmaceutically acceptableexcipient, carrier, or diluent, wherein formula (II) is:

or a pharmaceutically acceptable salt thereof, wherein

-   A represents aryl optionally substituted with one, two, three, or    four groups that are each independently halogen, cyano, nitro, C₁₋₆    alkyl, C_(l-6) haloalkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂,    —OH, C₁-C₆ alkoxy, and C₁-C₆ haloalkoxy;-   X is a bond, —CH₂—, —CHR⁵, —C═CHR⁴—, —NR⁴—, —N═O—R⁴—, —O—, —S—,    —SO—, —SO₂—, —C(O)—, —C(S)—, —C(CH₂)—, —C(NR⁴)—, —C(O)CH₂O—,    —CH(OR⁴)CH₂O—, —C(NR⁴)CH₂O—, or —CH(N(R⁴)₂)CH₂O—, or X is of formula

wherein

-   -   each n is independently 1, 2, or 3;    -   each R⁴ is independently hydrogen or C₁₋₆ alkyl;    -   R⁵ is independently hydrogen, C₁₋₆ alkyl, or —OR⁶, where R⁶ is        selected from the group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₃₋₁₂ cycloalkyl, heterocyclyl, aryl,        arylC₁₋₆ alkyl, heteroaryl, or heteroarylC₁₋₆ alkyl;

-   Y is C₁₋₆ alkylene, C₂₋₆ alkenylene, or C₂₋₆ alkylylene moiety;

-   R¹ is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ haloalkyl, C₃₋₁₂ cycloalkyl,    heterocyclyl, aryl, arylC₁₋₆ alkyl, heteroaryl, or heteroarylC₁₋₆    alkyl, wherein the alkyl, aryl, arylalkyl, heteroaryl, and    heteroarylalkyl are optionally substituted with one, two, three, or    four groups that are each independently halogen, cyano, nitro, C₁₋₆    alkyl, C₁₋₆ haloalkyl, —OR⁷, —SR⁷, —N(R⁷)₂, —C(O)R⁷, —C(O)OR⁷,    —C(O)N(R⁷)₂, —S(O)₂R⁷, —OC(O)R⁷, —OC(O)OR⁷, —OC(O)N(R⁷)₂,    —N(R⁷)C(O)R⁷, —N(R⁷)C(O)OR⁷, or —N(R⁷)C(O)N(R⁷)₂, wherein each R⁷ is    independently hydrogen or C₁₋₆ alkyl;

-   R² is hydrogen, halogen, C₁₋₆ alkyl, or —OR⁸, where R⁸ is selected    from the group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl,    C₂₋₆ alkynyl, C₃₋₁₂ cycloalkyl, heterocyclyl, aryl, arylC₁₋₆ alkyl,    heteroaryl, or heteroarylC₁₋₆ alkyl, wherein the alkyl, aryl,    arylalkyl, heteroaryl, and heteroarylalkyl are optionally    substituted with one, two, three, or four groups that are each    independently halogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl,    —OR⁷, —SR⁷, —N(R⁷)₂, —C(O)R⁷, —C(O)OR⁷, —C(O)N(R⁷)₂, —S(O)₂R⁷,    —OC(O)R⁷, —OC(O)OR⁷, —OC(O)N(R⁷)₂, —N(R⁷)C(O)R⁷, —N(R⁷)C(O)OR⁷, or    —N(R⁷)C(O)N(R⁷)₂, wherein each R⁷ is independently hydrogen or C₁₋₆    alkyl;

-   or R¹ and R² together with the atoms to which they are attached form    a C₃₋₁₂ cycloalkyl, heterocyclyl, aryl, or heteroaryl, each    optionally substituted with one, two, three, or four groups that are    each independently halogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆    haloalkyl, —OR⁷, —SR⁷, —N(R⁷)₂, —C(O)R⁷, —C(O)OR⁷, —C(O)N(R⁷)₂,    —S(O)₂R⁷, —OC(O)R⁷, —OC(O)OR⁷, —OC(O)N(R⁷)₂, —N(R⁷)C(O)R⁷,    —N(R⁷)C(O)OR⁷, or —N(R⁷)-C(O)N(R⁷)₂; and

-   R³ is hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —OR, —SR, or —NR₂,    -   and each R is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl,        C₁₋₆ haloalkyl, C₃₋₁₂ cycloalkyl, heterocyclyl, aryl, arylC₁₋₆        alkyl, heteroaryl, or heteroarylC₁₋₆ alkyl, wherein the alkyl,        aryl, arylalkyl, heteroaryl, and heteroarylalkyl are optionally        substituted with one, two, three, or four groups that are each        independently halogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl,        —OR⁰, —SR⁰, —N(R⁰)₂, —C(O)R⁰, —C(O)OR⁰, —C(O)N(R⁰)₂, —S(O)₂R⁰,        —OC(O)R⁰, —OC(O)OR⁰, —OC(O)N(R⁰)₂, —N(R⁰)C(O)R⁰, —N(R⁰)C(O)OR⁰,        or —N(R⁰)C(O)N(R⁰)₂, wherein each R⁰ is independently hydrogen        or C₁₋₆ alkyl.

In other aspect, the diseases ameliorated by the inhibition of CYP26mediated retinoic acid metabolism are cancer, such as (but not limitedto) acute promyelocytic leukaemia, neuroblastoma, basal cell andsquamous cell carcinomas, prostate cancer, lung cancer, and breastcancer; neurodegenerative diseases, such as (but not limited to)Alzheimer's disease, Parkinson's disease and stroke; and dermatologicaldisorders, such as (but not limited to) acne, psoriasis, and ichthyosis.

In further aspect of the present disclosure, the compounds of formula(I) or (II) are capable of selective inhibition of CYP26A1 over CYP26B1.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows characterization of 9cis-RA as a substrate of CYP26B1. UVchromatograms of 9cisRA incubated with CYP26B1 in the presence andabsence of NADPH are shown in panel A. Panel B shows the determinationof the Michaelis Menten kinetic constants for 9-cis-4OH-RA formationfrom 9-cis-RA by CYP26B1.

FIG. 2 illustrates azole IC₅₀'s and K_(d)'s with CYP26B1.

FIG. 3 illustrates tazarotenic acid and tazarotene IC₅₀'s with A1 and B1ester versus acid for 2 and 5 and 1 and 4 with 26B1.

FIG. 4 shows the activity of NOH-containing compounds.

DETAILED DESCRIPTION OF THE INVENTION

The following description provides specific details for a thoroughunderstanding of, and enabling description for, embodiments of thedisclosure. However, one skilled in the art will understand that thedisclosure may be practiced without these details. In other instances,well-known structures and functions have not been shown or described indetail to avoid unnecessarily obscuring the description of theembodiments of the disclosure.

In view of the present disclosure, the compounds described herein can beconfigured by the person of ordinary skill in the art to meet thedesired need. In general, the disclosed compounds provide improvementsin treatment of diseases that are ameliorated by the inhibition of CYP26mediated retinoic acid metabolism. For example, in certain aspects, thecompounds of the disclosure are effective against disorders, includingcancers, such as (but not limited to) acute promyelocytic leukaemia,neuroblastoma, basal cell and squamous cell carcinomas, lung, prostatecancer, and breast cancer; neurodegenerative diseases, such as (but notlimited to) Alzheimer's disease, Parkinson's disease and stroke; anddermatological disorders, such as (but not limited to) acne, psoriasis,and ichthyosis. Furthermore, the compounds of the disclosure may havethe advantage of avoiding side effects usually caused by retinoids, suchas skin irritation, teratogenesis, and/or hypervitaminosis-A. Finally,the compounds of the disclosure are capable of selective inhibition ofCYP26A1 over CYP26B1.

In one embodiment, the compounds of formula (I) or (II) are those whereA is optionally substituted phenyl. Such compound can be represented byformula:

In other embodiments, when A is optionally substituted phenyl, compoundsare of formula:

In some other embodiments, when A is optionally substituted phenyl,compounds are of formula:

In one embodiment, the compounds of formula (I) or (II) are those whereA is optionally substituted naphthyl. Such compound can be representedby formula:

In other embodiments, when A is optionally substituted naphthyl,compounds are of formula:

In some other embodiments, when A is optionally substituted naphthyl,compounds are of formula:

In one embodiment, the compounds of formula (I) or (II) and anypreceding embodiment are those where:

-   X is —CH₂—, —CHR⁵—, —C═CHR⁴—, —NR⁴—, —N═O—R⁴—, —O—, —S—, —SO—,    —SO₂—, —C(O)—, or —C(NR⁴)—, or X is of formula

wherein

-   -   each n is independently 1, 2, or 3;    -   each R⁴ is independently hydrogen or C₁₋₆ alkyl; and    -   R⁵ is independently hydrogen, C₁₋₆ alkyl, or —OR⁶, where R⁶ is        selected from the group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₃₋₁₂ cycloalkyl, heterocyclyl, aryl,        arylC₁₋₆ alkyl, heteroaryl, or heteroarylC₁₋₆ alkyl.

In another embodiment, the compounds of formula (I) or (II) and anypreceding embodiment are those where X is —CH₂—, —CHR⁵—, —C═CHR⁴—,—NR⁴—, —N═O—R⁴—, —O—, —S—, —SO—, —SO₂—, —C(O)—, or —C(NR⁴)—, wherein

-   each R⁴ is independently hydrogen or C₁₋₆ alkyl; and-   R⁵ is independently hydrogen, C₁₋₆ alkyl, or —OR⁶, where R⁶ is    selected from the group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆    alkenyl, C₂₋₆ alkynyl, C₃₋₁₂ cycloalkyl, heterocyclyl, aryl,    arylC₁₋₆ alkyl, heteroaryl, or heteroarylC₁₋₆ alkyl.

Other particularly useful compounds of formula (I) or (II) and anypreceding embodiment are those where X is —CH₂— or —CHR⁵—, wherein R⁵ isindependently hydrogen, C₁₋₆ alkyl, or —OR⁶, where R⁶ is selected fromthe group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₂ cycloalkyl, heterocyclyl, aryl, arylC₁₋₆ alkyl,heteroaryl, or heteroarylC₁₋₆ alkyl. In other embodiments, X is —CH₂—.Compounds of formula (I) or (II), in one embodiment, include those whereX is —NR⁴ ₂—, —O—, —S—, —SO—, —SO₂—, —C(O)—, or —C(NR⁴)—, wherein eachR⁴ is independently hydrogen or C₁₋₆ alkyl. Certain embodiments of thecompounds of the disclosure include those where X is —O—, —S—, —SO—,—SO₂—, —C(O)—, or —C(NR⁴)—. In some embodiments, X is —O—, —S—, —SO—, or—SO₂—. In other embodiments, X is —O—. In one embodiment of thedisclosure, the compounds are those where X is —S—, —SO—, or —SO₂—. Inanother embodiment of the disclosure, the compounds are those where X is—C(O)—.

Other particularly useful compounds of formula (I) or (II) and anypreceding embodiment are those where X is of formula

and each n is independently 1 or 2. In one embodiment, each n isindependently 1. In another embodiment, X is

in yet another embodiment, X is of formula

and each n is independently 1 or 2; or each n is independently 1.

Other particularly useful compounds of formula (I) or (II) are thosewhere X is a bond.

Certain embodiments of the compounds of the disclosure include thosewhere X is a bond, —CH₂—, —NH—, —S—, —SO₂—, —C(O)—,

Certain other embodiments of the compounds of the disclosure includethose where X is —CH₂—, —NH—, —S—, —SO₂—, —C(O)—,

Compounds of formula (I) or (II) and any previous embodiment includecompounds wherein Y is C₁₋₆ alkylene or C₂₋₆ alkenylene. In someembodiments, Y is C₁₋₄ alkylene or C₂₋₄ alkenylene. In some otherembodiments, Y is C₁₋₄ alkylene. For example, Y may be methylene,ethylene, or propylene. In other embodiments, Y is methylene and/orethylene. In one embodiment of the disclosure, the compounds are thosewhere Y is C₂₋₄ alkenylene. In one embodiment, Y is —CH═CH—, —CH₂CH═CH—,or —CH═CHCH₂—.

Compounds of formula (I) or (II) and any previous embodiment includecompounds wherein Y is methylene, ethylene, or —CH═CH—.

Other particularly useful compounds of formula (I) or (II) and anypreceding embodiment are those where R³ is hydrogen, C₁₋₆ alkyl, —OR, or—NR₂, and each R is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₁₋₆ haloalkyl, C₃₋₁₂ cycloalkyl, heterocyclyl, aryl, arylC₁₋₆ alkyl,heteroaryl, or heteroarylC₁₋₆ alkyl, wherein the alkyl, aryl, arylalkyl,heteroaryl, and heteroarylalkyl are optionally substituted with one,two, three, or four groups that are each independently halogen, cyano,nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —OR⁰, —SR⁰, —N(R⁰)₂, —C(O)R⁰,—C(O)OR⁰, —C(O)N(R⁰)₂, —S(O)₂R⁰, —OC(O)R⁰, —OC(O)OR⁰, —OC(O)N(R⁰)₂,—N(R⁰)C(O)R⁰, —N(R⁰)C(O)OR⁰, or —N(R⁰)C(O)N(R⁰)₂, wherein each R⁰ isindependently hydrogen or C₁₋₆ alkyl. In some embodiments, R³ ishydrogen or C₁₋₆ alkyl. In other embodiments, R³ is hydrogen. In oneembodiment of the disclosure, the compounds are those where R³ is C₁₋₆alkyl. For example, R³ may be methyl, ethyl, propyl, isopropyl, butyl,secbutyl, isobutyl, and tertbutyl. In one embodiment, R³ may be methyl,ethyl, propyl, or isopropyl. In a particular embodiment, R³ is methyl.

Certain other embodiments of the compounds of the disclosure (and anypreceding embodiments) include those where R³ is —NR₂. In someembodiments, each R is independently hydrogen or C₁₋₆ alkyl optionallysubstituted with one, two, three, or four groups that are eachindependently halogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —OR⁰,—SR⁰, —N(R⁰)₂, —C(O)R⁰, —C(O)OR⁰, —C(O)N(R⁰)₂, —S(O)₂R⁰, —OC(O)R⁰,—OC(O)OR⁰, —OC(O)N(R⁰)₂, —N(R⁰)C(O)R⁰, —N(R⁰)C(O)OR⁰, or—N(R⁰)C(O)N(R⁰)₂, wherein each R⁰ is independently hydrogen or C₁₋₆alkyl. In some embodiments, each R is independently hydrogen or C₁₋₆alkyl. In some other embodiments, each R is independently hydrogen ormethyl.

Other embodiments of the compounds of the disclosure (and any precedingembodiments) include those where R³ is —OR. In some embodiments, R ishydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ haloalkyl, C₃₋₁₂ cycloalkyl,heterocyclyl, aryl, arylC₁₋₆ alkyl, heteroaryl, or heteroarylC₁₋₆ alkyl,wherein the alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl areoptionally substituted with one, two, three, or four groups that areeach independently halogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl,—OR⁰, —SR⁰, —N(R⁰)₂, —C(O)R⁰, —C(O)OR⁰, —C(O)N(R⁰)₂, and —S(O)₂R⁰,wherein each R⁰ is independently hydrogen or C₁₋₆ alkyl. In otherembodiments, R is hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₂cycloalkyl, aryl, arylC₁₋₆ alkyl, heteroaryl, or heteroarylC₁₋₆ alkyl,wherein the alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl areoptionally substituted with one, two, three, or four groups that areeach independently halogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl,—OR⁰, —SR⁰, —N(R⁰)₂, —C(O)R⁰, —C(O)OR⁰, —C(O)N(R⁰)₂, and —S(O)₂R⁰,wherein each R⁰ is independently hydrogen or C₁₋₆ alkyl. In yet otherembodiments, R is hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, or arylC₁₋₆alkyl, wherein the alkyl and arylalkyl are optionally substituted withone, two, three, or four groups that are each independently halogen,cyano, nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —OR⁰, —SR⁰, —N(R⁰)₂, —C(O)R⁰,—C(O)OR⁰, —C(O)N(R⁰)₂, and —S(O)₂R⁰, wherein each R⁰ is independentlyhydrogen or C₁₋₆ alkyl.

Some particularly useful compounds of formula (I) or (II) and anypreceding embodiment are those where R³ is —OR, and R is hydrogen orC₁₋₆ alkyl. In one embodiment, R is hydrogen. In another embodiment, Ris C₁₋₄ alkyl. For example, R may be methyl, ethyl, propyl, isopropyl,butyl, secbutyl, isobutyl, and tertbutyl. In one embodiment, R may bemethyl, ethyl, propyl, or isopropyl. In a particular embodiment, R ismethyl. In another embodiment, R is hydrogen, methyl, ethyl, propyl, orbutyl.

Some other particularly useful compounds of formula (I) or (II) and anypreceding embodiment are those where R³ is —OR, and R is arylC₁₋₆ alkyl.For example, R may be benzyl.

In another embodiment, the compounds of formula (I) or (II) and anypreceding embodiment are those where R¹ and R² together with the atomsto which they are attached form a C₃₋₁₂ cycloalkyl, heterocyclyl, aryl,or heteroaryl, each optionally substituted with one, two, three, or fourgroups that are each independently halogen, cyano, nitro, C₁₋₆ alkyl,C₁₋₆ haloalkyl, —OR⁷, —SR⁷, —N(R⁷)₂, —C(O)R⁷, —C(O)OR⁷, —C(O)N(R⁷)₂,—S(O)₂R⁷, —OC(O)R⁷, —OC(O)OR⁷, —OC(O)N(R⁷)₂, —N(R⁷)C(O)R⁷,—N(R⁷)C(O)OR⁷, or —N(R⁷)C(O)N(R⁷)₂. For example, one embodiment providescompounds where R¹ and R² together with the atoms to which they areattached form a C₃₋₁₂ cycloalkyl, optionally substituted with one, two,three, or four groups that are each independently halogen, cyano, nitro,C₁₋₆ alkyl, C₁₋₆ haloalkyl, —OR⁷, —SR⁷, —N(R⁷)₂, —C(O)R⁷, —C(O)OR⁷,—C(O)N(R⁷)₂, —S(O)₂R⁷, —OC(O)R⁷, —OC(O)OR⁷, —OC(O)N(R⁷)₂, —N(R⁷)C(O)R⁷,—N(R⁷)C(O)OR⁷, or —N(R⁷)C(O)N(R⁷)₂. Another embodiment providescompounds where R¹ and R² together with the atoms to which they areattached form a cyclohexane, optionally substituted with one, two,three, or four groups that are each independently halogen, cyano, nitro,C₁₋₆ alkyl, C₁₋₆ haloalkyl, —OR⁷, —SR⁷, —N(R⁷)₂, —C(O)R⁷, —C(O)OR⁷,—C(O)N(R⁷)₂, —S(O)₂R⁷, —OC(O)R⁷, —OC(O)OR⁷, —OC(O)N(R⁷)₂, —N(R⁷)C(O)R⁷,—N(R⁷)C(O)OR⁷, or —N(R⁷)C(O)N(R⁷)₂. Some particularly useful compoundsare those wherein R¹ and R² together with the atoms to which they areattached form a cyclohexane substituted with four C₁₋₆ alkyl groups. Forexample, R¹ and R² together with the atoms to which they are attachedform:

In another embodiment, the compounds of formula (I) or (II) and anypreceding embodiment are those where R¹ and R² represent:

-   R¹ is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ haloalkyl, C₃₋₁₂ cycloalkyl,    heterocyclyl, aryl, arylC₁₋₆ alkyl, heteroaryl, or heteroarylC₁₋₆    alkyl, wherein the alkyl, aryl, arylalkyl, heteroaryl, and    heteroarylalkyl are optionally substituted with one, two, three, or    four groups that are each independently halogen, cyano, nitro, C₁₋₆    alkyl, C₁₋₆ haloalkyl, —OR⁷, —SR⁷, —N(R⁷)₂, —C(O)R⁷, —C(O)OR⁷,    —C(O)N(R⁷)₂, —S(O)₂R⁷, —OC(O)R⁷, —OC(O)OR⁷, —OC(O)N(R⁷)₂,    —N(R⁷)C(O)R⁷, —N(R⁷)C(O)OR⁷, or —N(R⁷)C(O)N(R⁷)₂, wherein each R⁷ is    independently hydrogen or C₁₋₆ alkyl; and-   R² is hydrogen, halogen, C₁₋₆ alkyl, or —OR⁸, where R⁸ is selected    from the group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl,    C₂₋₆ alkynyl, C₃₋₁₂ cycloalkyl, heterocyclyl, aryl, arylC₁₋₆ alkyl,    heteroaryl, or heteroarylC₁₋₆ alkyl, wherein the alkyl, aryl,    arylalkyl, heteroaryl, and heteroarylalkyl are optionally    substituted with one, two, three, or four groups that are each    independently halogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl,    —OR⁷, —SR⁷, —N(R⁷)₂, —C(O)R⁷, —C(O)OR⁷, —C(O)N(R⁷)₂, —S(O)₂R⁷,    —OC(O)R⁷, —OC(O)OR⁷, —OC(O)N(R⁷)₂, —N(R⁷)C(O)R⁷, —N(R⁷)C(O)OR⁷, or    —N(R⁷)C(O)N(R⁷)₂, wherein    -   each R⁷ is independently hydrogen or C₁₋₆ alkyl.        Some particularly useful compounds this embodiment are those        where R¹ is C₁₋₆ alkyl, C₃₋₁₂ cycloalkyl, heterocyclyl, aryl,        arylC₁₋₆ alkyl, heteroaryl, or heteroarylC₁₋₆ alkyl, wherein the        alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl are        optionally substituted with one, two, three, or four groups that        are each independently halogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆        haloalkyl, —OR⁷, —SR⁷, —N(R⁷)₂, —C(O)R⁷, —C(O)OR⁷, —C(O)N(R⁷)₂,        —S(O)₂R⁷, —OC(O)R⁷, —OC(O)OR⁷, —OC(O)N(R⁷)₂, —N(R⁷)C(O)R⁷,        —N(R⁷)C(O)OR⁷, or —N(R⁷)C(O)N(R⁷)₂, wherein each R⁷ is        independently hydrogen or C₁₋₆ alkyl. Other particularly useful        compounds are those wherein R¹ is C₁₋₆ alkyl, C₃₋₁₂ cycloalkyl,        or arylC₁₋₆ alkyl, wherein the alkyl and arylalkyl, heteroaryl        are optionally substituted with one, two, three, or four groups        that are each independently halogen, cyano, nitro, C₁₋₆ alkyl,        C₁₋₆ haloalkyl, —OR⁷, —SR⁷, —N(R⁷)₂, —C(O)R⁷, —C(O)OR⁷,        —C(O)N(R⁷)₂, —S(O)₂R⁷, —OC(O)R⁷, —OC(O)OR⁷, —OC(O)N(R⁷)₂,        —N(R⁷)C(O)R⁷, —N(R⁷)C(O)OR⁷, or —N(R⁷)C(O)N(R⁷)₂, wherein each        R⁷ is independently hydrogen or C₁₋₆ alkyl. In another        embodiment, R¹ is C₁₋₆ alkyl or C₃₋₁₂ cycloalkyl, each        optionally substituted with one, two, three, or four groups that        are each independently halogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆        haloalkyl, —OR⁷, —SR⁷, —N(R⁷)₂, —C(O)R⁷, —C(O)OR⁷, —C(O)N(R⁷)₂,        —S(O)₂R⁷, —OC(O)R⁷, —OC(O)OR⁷, —OC(O)N(R⁷)₂, —N(R⁷)C(O)R⁷,        —N(R⁷)C(O)OR⁷, or —N(R⁷)C(O)N(R⁷)₂, wherein each R⁷ is        independently hydrogen or C₁₋₆ alkyl.

In one embodiment, the compounds of formula (I) or (II) and anypreceding embodiment are those wherein R¹ is optionally substituted C₁₋₆alkyl. In one embodiment, R¹ is unsubstituted C₁₋₆ alkyl. For example,R¹ may be methyl, ethyl, propyl, isopropyl, butyl, secbutyl, isobutyl,and tertbutyl. In one embodiment, R¹ is tert-butyl.

In one embodiment, the compounds of formula (I) or (II) and anypreceding embodiment are those wherein R¹ is optionally substitutedC₃₋₁₂ cycloalkyl. In one embodiment, R¹ is unsubstituted C₃₋₁₂cycloalkyl. In one embodiment, for example, R¹ is adamantyl.

Another embodiment provides the compounds of formula (I) or (II) and anypreceding embodiment wherein R² is halogen, C₁₋₆ alkyl, or —OR⁸. Someparticularly useful compounds this embodiment are those where R² ishalogen or C₁₋₆ alkyl. Some other particularly useful compounds thisembodiment are those where R² is —OR⁸. In one embodiment, R⁸ is selectedfrom the group consisting of hydrogen, C₁₋₆ alkyl, C₃₋₁₂ cycloalkyl,heterocyclyl, aryl, arylC₁₋₆ alkyl, heteroaryl, or heteroarylC₁₋₆ alkyl,wherein the alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl areoptionally substituted with one, two, three, or four groups that areeach independently halogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl,—OR⁷, —SR⁷, —N(R⁷)₂, —C(O)R⁷, —C(O)OR⁷, —C(O)N(R⁷)₂, —S(O)₂R⁷, —OC(O)R⁷,—OC(O)OR⁷, —OC(O)N(R⁷)₂, —N(R⁷)C(O)R⁷, —N(R⁷)C(O)OR⁷, or—N(R⁷)C(O)N(R⁷)₂, wherein each R⁷ is independently hydrogen or C₁₋₆alkyl. In another embodiment, R⁸ is selected from the group consistingof hydrogen, C₁₋₆ alkyl, or arylC₁₋₆ alkyl, wherein the alkyl andarylalkyl are optionally substituted with one, two, three, or fourgroups that are each independently halogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —OR⁷, —SR⁷, —N(R⁷)₂, —C(O)R⁷, —C(O)OR⁷, —C(O)N(R⁷,—S(O)₂R⁷, —OC(O)R⁷, —OC(O)OR⁷, —OC(O)N(R⁷)₂, —N(R⁷)C(O)R⁷,—N(R⁷)C(O)OR⁷, or —N(R⁷)C(O)N(R⁷)₂, wherein each R⁷ is independentlyhydrogen or C₁₋₆ alkyl. In yet another embodiment, R⁸ is of hydrogen orC₁₋₆ alkyl.

In one embodiment, the compounds any preceding embodiment are thoseWherein R² is —OR⁸, and R⁸ is of hydrogen. In another embodiment, thecompounds any preceding embodiment are those wherein R² is —OR⁸, and R⁸is of C₁₋₆ alkyl. In another embodiment, the compounds any precedingembodiment are those wherein R² is —OR⁸, and R⁸ is of hydrogen ormethyl. In yet another embodiment, the compounds any precedingembodiment are those wherein R² is —OR⁸, and R⁸ is of arylC₁₋₆ alkyl.For example, R⁸ may be benzyl. In yet another embodiment, the compoundsany preceding embodiment are those wherein R² is —OR⁸, and R⁸ ishydrogen, C₁₋₆ alkyl, or benzyl.

The compounds of the disclosure are capable of inhibiting the activityof CYP26, and consequently acting as an RA metabolism blocking agents.Inhibition of CYP26 may be either in vivo and/or in vitro. Accordingly,the disclosure provides methods for treating diseases that areameliorated by the inhibition of CYP26 mediated retinoic acid metabolismcomprising providing to a patient in need of such treatment atherapeutically effective amount of either a compound of the disclosure(e.g., compounds formula (I) or (II) or any preceding embodiment), or apharmaceutical composition comprising one or more of compounds of thedisclosure. The diseases ameliorated by the inhibition of CYP26 mediatedretinoic acid metabolism are cancer, such as (but not limited to) acutepromyelocytic leukaemia, neuroblastoma, basal cell and squamous cellcarcinomas, prostate cancer, lung cancer, and breast cancer;neurodegenerative diseases, such as (but not limited to) Alzheimer'sdisease, Parkinson's disease and stroke; and dermatological disorders,such as (but not limited to) acne, psoriasis, and ichthyosis.

The disclosure also provides methods for selectively inhibiting CYP26A1over CYP26B1, comprising providing to a patient a therapeuticallyeffective amount of either a compound of the disclosure (e.g., compoundsformula (I) or (II) or any preceding embodiment), or a pharmaceuticalcomposition comprising one or more of compounds of the disclosure.

The disclosure also provides methods for treating diseases that areameliorated by administration of retinoic acid comprising providing to apatient in need of such treatment a therapeutically effective amount ofeither a compound of the disclosure (e.g., compounds formula (I) or (II)or any preceding embodiments) in combination with retinoic acid, or apharmaceutical composition comprising one or more of compounds of thedisclosure in combination with retinoic acid.

As used herein, the term “subject”, “individual,” or “patient,” usedinterchangeably, refers to any animal, including mammals, such as mice,rats, other rodents, rabbits, dogs, cats, birds, swine, horses,livestock (e.g., pigs, sheep, goats, cattle), primates or humans. In oneembodiment, the patient is a human.

As used here, a subject “in need thereof” refers to a subject that hasthe disorder or disease to be treated or is predisposed to or otherwiseat risk of developing the disease or disorder.

As used here, the terms “treatment” and “treating” means:

-   (i) inhibiting the progression the disease;-   (ii) prophylactic use for example, preventing or limiting    development of a disease, condition or disorder in an individual who    may be predisposed or otherwise at risk to the disease, condition or    disorder but does not yet experience or display the pathology or    symptomatology of the disease;-   (iii) inhibiting the disease; for example, inhibiting a disease,    condition or disorder in an individual who is experiencing or    displaying the pathology or symptomatology of the disease, condition    or disorder;-   (iv) ameliorating the referenced disease state, for example,    ameliorating a disease, condition or disorder in an individual who    is experiencing or displaying the pathology or symptomatology of the    disease, condition or disorder (i.e., reversing or improving the    pathology and/or symptomatology) such as decreasing the severity of    disease; or-   (v) eliciting the referenced biological effect.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response that is being sought in a tissue,system, animal, individual or human by a researcher, veterinarian,medical doctor or other clinician, which includes one or more of thefollowing: (1) preventing the disease; for example, preventing adisease, condition or disorder in an individual who may be predisposedto the disease, condition or disorder but does not yet experience ordisplay the pathology or symptomatology of the disease; (2) inhibitingthe disease; for example, inhibiting a disease, condition or disorder inan individual who is experiencing or displaying the pathology orsymptomatology of the disease, condition or disorder; and (3)ameliorating the disease; for example, ameliorating a disease, conditionor disorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,reversing the pathology and/or symptomatology) such as decreasing theseverity of disease.

The pharmaceutical compositions described herein generally comprise acombination of one or more of compounds described herein and apharmaceutically acceptable carrier, diluent, or excipient. Suchcompositions are substantially free of non-pharmaceutically acceptablecomponents, i.e., contain amounts of non-pharmaceutically acceptablecomponents lower than permitted by US regulatory requirements at thetime of filing this application. In some embodiments of this aspect, ifthe compound is dissolved or suspended in water, the composition furtheroptionally comprises an additional pharmaceutically acceptable carrier,diluent, or excipient. In one embodiment, the pharmaceuticalcompositions described herein are solid pharmaceutical compositions(e.g., tablet, capsules, etc.).

These compositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is desired and uponthe area to be treated. Administration may be topical (includingophthalmic and to mucous membranes including intranasal, vaginal andrectal delivery), pulmonary (e.g., by inhalation or insufflation ofpowders or aerosols, including by nebulizer; intratracheal, intranasal,epidermal and transdermal), ocular, oral or parenteral. Methods forocular delivery can include topical administration (eye drops),subconjunctival, periocular or intravitreal injection or introduction byballoon catheter or ophthalmic inserts surgically placed in theconjunctival sac. Parenteral administration includes intravenous,intraarterial, subcutaneous, intraperitoneal or intramuscular injectionor infusion; or intracranial, e.g., intrathecal or intraventricular,administration. Parenteral administration can be in the form of a singlebolus dose, or may be, for example, by a continuous perfusion pump.Pharmaceutical compositions and formulations for topical administrationmay include transdermal patches, ointments, lotions, creams, gels,drops, suppositories, sprays, liquids and powders. Conventionalpharmaceutical carriers, aqueous, powder or oily bases, thickeners andthe like may be necessary or desirable.

Also, pharmaceutical compositions can contain, as the active ingredient,one or more of the compounds described herein above in combination withone or more pharmaceutically acceptable carriers. In making thecompositions described herein, the active ingredient is typically mixedwith an excipient, diluted by an excipient or enclosed within such acarrier in the form of, for example, a capsule, sachet, paper, or othercontainer. When the excipient serves as a diluent, it can be a solid,semi-solid, or liquid material, which acts as a vehicle, carrier ormedium for the active ingredient. Thus, the compositions can be in theform of tablets, pills, powders, lozenges, sachets, cachets, elixirs,suspensions, emulsions, solutions, syrups, aerosols (as a solid or in aliquid medium), ointments containing, for example, up to 10% by weightof the active compound, soft and hard gelatin capsules, suppositories,sterile injectable solutions, and sterile packaged powders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g. about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions described herein can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 100 mg, more usually about 10 to about30 mg, of the active ingredient. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound described herein. When referring to these preformulationcompositions as homogeneous, the active ingredient is typicallydispersed evenly throughout the composition so that the composition canbe readily subdivided into equally effective unit dosage forms such astablets, pills and capsules. This solid preformulation is thensubdivided into unit dosage forms of the type described above containingfrom, for example, 0.1 to about 500 mg of the active ingredient of acompound described herein.

The tablets or pills can be coated or otherwise compounded to provide adosage form affording the advantage of prolonged action. For example,the tablet or pill can comprise an inner dosage and an outer dosagecomponent, the latter being in the form of an envelope over the former.The two components can be separated by an enteric layer which serves toresist disintegration in the stomach and permit the inner component topass intact into the duodenum or to be delayed in release. A variety ofmaterials can be used for such enteric layers or coatings, suchmaterials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol, andcellulose acetate.

The liquid forms in which the compounds and compositions can beincorporated for administration orally or by injection include aqueoussolutions, suitably flavored syrups, aqueous or oil suspensions, andflavored emulsions with edible oils such as cottonseed oil, sesame oil,coconut oil, or peanut oil, as well as elixirs and similarpharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions in can be nebulized by use of inert gases. Nebulizedsolutions may be breathed directly from the nebulizing device or thenebulizing device can be attached to a face masks tent, or intermittentpositive pressure breathing machine. Solution, suspension, or powdercompositions can be administered orally or nasally from devices whichdeliver the formulation in an appropriate manner.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of the compounds can vary according to, forexample,the particular use for which the treatment is made, the mannerof administration of the compound, the health and condition of thepatient, and the judgment of the prescribing physician. The proportionor concentration of a compound described herein in a pharmaceuticalcomposition can vary depending upon a number of factors includingdosage, chemical characteristics (e.g., hydrophobicity), and the routeof administration. For example, the compounds described herein can beprovided in an aqueous physiological buffer solution containing about0.1 to about 10% w/v of the compound for parenteral administration. Sometypical dose ranges are from about 1 μg/kg to about 1 g/kg of bodyweight per day. In some embodiments, the dose range is from about 0.01mg/kg to about 100 mg/kg of body weight per day. The dosage is likely todepend on such variables as the type and extent of progression of thedisease or disorder, the overall health status of the particularpatient, the relative biological efficacy of the compound selected,formulation of the excipient, and its route of administration. Effectivedoses can be extrapolated from dose-response curves derived from invitro or animal model test systems.

The compounds described herein can also be formulated in combinationwith one or more additional active ingredients which can include anypharmaceutical agent such as anti-viral agents, vaccines, antibodies,immune enhancers, immune suppressants, anti-inflammatory agents and thelike.

Definitions

Unless the context clearly requires otherwise, throughout thedescription and the claims, the words ‘comprise’, ‘comprising’, and thelike are to be construed in an inclusive sense as opposed to anexclusive or exhaustive sense; that is to say, in the sense of“including, but not limited to”. Words using the singular or pluralnumber also include the plural or singular number, respectively.Additionally, the words “herein,” “above” and “below” and words ofsimilar import, when used in this application, shall refer to thisapplication as a whole and not to any particular portions of thisapplication.

Terms used herein may be preceded and/or followed by a single dash, “-”,or a double dash, “═”, to indicate the bond order of the bond betweenthe named substituent and its parent moiety; a single dash indicates asingle bond and a double dash indicates a double bond. In the absence ofa single or double dash it is understood that a single bond is formedbetween the substituent and its parent moiety; further, substituents areintended to be read “left to right” unless a dash indicates otherwise.For example, C₁₋₆alkoxycarbonyloxy and —OC(O)C₁-C₆alkyl indicate thesame functionality; similarly arylalkyl and -alkylaryl indicate the samefunctionality.

The term “alkenyl” as used herein, means a straight or branched chainhydrocarbon containing from 2 to 10 carbons, unless otherwise specified,and containing at least one carbon-carbon double bond. Representativeexamples of alkenyl include, but are not limited to, ethenyl,2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl,2-heptenyl, 2-methyl-1-heptenyl, 3-decenyl, and3,7-dimethylocta-2,6-dienyl.

The term “alkyl” as used herein, means a straight or branched chainhydrocarbon containing from 1 to 10 carbon atoms, unless otherwisespecified. Representative examples of alkyl include, but are not limitedto, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, andn-decyl. When an “alkyl” group is a linking group between two othermoieties, then it may also be a straight or branched chain; examplesinclude, but are not limited to —CH₂—, —CH₂CH₂—, —CH₂CH₂CHC(CH₃)—,—CH₂CH(CH₂CH₃)CH₂—.

The term “alkynyl” as used herein, means a straight or branched chainhydrocarbon group containing from 2 to 10 carbon atoms and containing atleast one carbon-carbon triple bond. Representative examples of alkynylinclude, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl,3-butynyl, 2-pentynyl, and 1-butynyl.

The term “aryl,” as used herein, means a phenyl (i.e., monocyclic aryl),a bicyclic ring system containing at least one phenyl ring or anaromatic bicyclic ring containing only carbon atoms in the aromaticbicyclic ring system or a multicyclic aryl ring system, provided thatthe bicyclic or multicyclic aryl ring system does not contain aheteroaryl ring when fully aromatic. The bicyclic aryl can be azulenyl,naphthyl, or a phenyl fused to a monocyclic cycloalkyl, a monocycliccycloalkenyl, or a monocyclic heterocyclyl. The bicyclic aryl isattached to the parent molecular moiety through any carbon atomcontained within the phenyl portion of the bicyclic system, or anycarbon atom with the napthyl or azulenyl ring. The fused monocycliccycloalkyl or monocyclic heterocyclyl portions of the bicyclic aryl areoptionally substituted with one or two oxo and/or thia groups.Representative examples of the bicyclic aryls include, but are notlimited to, azulenyl, naphthyl, dihydroinden-1-yl, dihydroinden-2-yl,dihydroinden-3-yl, dihydroinden-4-yl, 2,3-dihydroindol-4-yl,2,3-dihydroindol-5-yl, 2,3-dihydroindol-6-yl, 2,3-dihydroindol-7-yl,inden-1-yl, inden-2-yl, inden-3-yl, inden-4-yl, dihydronaphthalen-2-yl,dihydronaphthalen-3-yl, dihydronaphthalen-4-yl, dihydronaphthalen-1-yl,5,6,7,8-tetrahydronaphthalen-1-yl, 5,6,7,8-tetrahydronaphthalen-2-yl,2,3-dihydrobenzofuran-4-yl, 2,3-dihydrobenzofuran-5-yl,2,3-dihydrobenzofuran-6-yl, 2,3-dihydrobenzofuran-7-yl,benzo[d][1,3]dioxol-4-yl, benzo[d][1,3]dioxol-5-yl,2H-chromen-2-on-5-yl, 2H-chromen-2-on-6-yl, 2H-chromen-2-on-7-yl,2H-chromen-2-on-8-yl, isoindoline-1,3-dion-4-yl,isoindoline-1,3-dion-5-yl, inden-1-on-4-yl, inden-1-on-5-yl,inden-1-on-6-yl, inden-1-on-7-yl, 2,3-dihydrobenzo[b][1,4]dioxan-5-yl,2,3-dihydrobenzo[b][1,4]dioxan-6-yl,2H-benzo[b][1,4]oxazin3(4H)-on-5-yl,2H-benzo[b][1,4]oxazin3(4H)-on-6-yl,2H-benzo[b][1,4]oxazin3(4H)-on-7-yl,2H-benzo[b][1,4]oxazin3(4H)-on-8-yl, benzo[d]oxazin-2(3H)-on-5-yl,benzo[d]oxazin-2(3H)-on-6-yl, benzo[d]oxazin-2(3H)-on-7-yl,benzo[d]oxazin-2(3H)-on-8-yl, quinazolin-4(3H)-on-5-yl,quinazolin-4(3H)-on-6-yl, quinazolin-4(3H)-on-7-yl,quinazolin-4(3H)-on-8-yl, quinoxalin-2(1H)-on-5-yl ,quinoxalin-2(1H)-on-6-yl, quinoxalin-2(1H)-on-7-yl,quinoxalin-2(1H)-on-8-yl, benzo[d]thiazol-2(3H)-on-4-yl,benzo[d]thiazol-2(3H)-on-5-yl, benzo[d]thiazol-2(3H)-on-6-yl, andbenzo[d]thiazol-2(3H)-on-7-yl. In certain embodiments, the bicyclic arylis (i) naphthyl or (ii) a phenyl ring fused to either a 5 or 6 memberedmonocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, or a 5or 6 membered monocyclic heterocyclyl, wherein the fused cycloalkyl,cycloalkenyl, and heterocyclyl groups are optionally substituted withone or two groups which are independently oxo or thia. Multicyclic arylgroups are a phenyl ring (base ring) fused to either (i) one ring systemselected from the group consisting of a bicyclic aryl, a bicycliccycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or(ii) two other ring systems independently selected from the groupconsisting of a phenyl, a bicyclic aryl, a monocyclic or bicycliccycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic orbicyclic heterocyclyl, provided that when the base ring is fused to abicyclic cycloalkyl, bicyclic cycloalkenyl, or bicyclic heterocyclyl,then the base ring is fused to the base ring of the a bicycliccycloalkyl, bicyclic cycloalkenyl, or bicyclic heterocyclyl. Themulticyclic aryl is attached to the parent molecular moiety through anycarbon atom contained within the base ring. In certain embodiments,multicyclic aryl groups are a phenyl ring (base ring) fused to either(i) one ring system selected from the group consisting of a bicyclicaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclicheterocyclyl; or (ii) two other ring systems independently selected fromthe group consisting of a phenyl, a monocyclic cycloalkyl, a monocycliccycloalkenyl, and a monocyclic heterocyclyl, provided that when the basering is fused to a bicyclic cycloalkyl, bicyclic cycloalkenyl, orbicyclic heterocyclyl, then the base ring is fused to the base ring ofthe a bicyclic cycloalkyl, bicyclic cycloalkenyl, or bicyclicheterocyclyl. Examples of multicyclic aryl groups include but are notlimited to anthracen-9-yl and phenanthren-9-yl.

The term “arylalkyl” and “-alkylaryl” as used herein, means an arylgroup, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofarylalkyl include, but are not limited to, benzyl, 2-phenylethyl,3-phenylpropyl, and 2-naphth-2-ylethyl.

The terms “cyano” and “nitrile” as used herein, mean a —CN group.

The term “cycloalkyl” as used herein, means a monocyclic, bicyclic, or amulticyclic cycloalkyl ring system. Monocyclic ring systems are cyclichydrocarbon groups containing from 3 to 8 carbon atoms, where suchgroups can be saturated or unsaturated, but not aromatic. In certainembodiments, cycloalkyl groups are fully saturated. Examples ofmonocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.Bicyclic cycloalkyl ring systems are bridged monocyclic rings or fusedbicyclic rings. Bridged monocyclic rings contain a monocyclic cycloalkylring where two non-adjacent carbon atoms of the monocyclic ring arelinked by an alkylene bridge of between one and three additional carbonatoms (i.e., a bridging group of the form —(CH₂)_(w)—, where w is 1, 2,or 3). Representative examples of bicyclic ring systems include, but arenot limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane,bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, andbicyclo[4.2.1]nonane. Fused bicyclic cycloalkyl ring systems contain amonocyclic cycloalkyl ring fused to either a phenyl, a monocycliccycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or amonocyclic heteroaryl. The bridged or fused bicyclic cycloalkyl isattached to the parent molecular moiety through any carbon atomcontained within the monocyclic cycloalkyl ring. Cycloalkyl groups areoptionally substituted with one or two groups which are independentlyoxo or thia. In certain embodiments, the fused bicyclic cycloalkyl is a5 or 6 membered monocyclic cycloalkyl ring fused to either a phenylring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 memberedmonocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a5 or 6 membered monocyclic heteroaryl, wherein the fused bicycliccycloalkyl is optionally substituted by one or two groups which areindependently oxo or thia. Multicyclic cycloalkyl ring systems are amonocyclic cycloalkyl ring (base ring) fused to either (i) one ringsystem selected from the group consisting of a bicyclic aryl, a bicyclicheteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and abicyclic heterocyclyl; or (ii) two other rings systems independentlyselected from the group consisting of a phenyl, a bicyclic aryl, amonocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl,a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclicheterocyclyl. The multicyclic cycloalkyl is attached to the parentmolecular moiety through any carbon atom contained within the base ring.In certain embodiments, multicyclic cycloalkyl ring systems are amonocyclic cycloalkyl ring (base ring) fused to either (i) one ringsystem selected from the group consisting of a bicyclic aryl, a bicyclicheteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and abicyclic heterocyclyl; or (ii) two other rings systems independentlyselected from the group consisting of a phenyl, a monocyclic heteroaryl,a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclicheterocyclyl. Examples of multicyclic cycloalkyl groups include, but arenot limited to tetradecahydrophenanthrenyl, perhydrophenothiazin-1-yl,and perhydrophenoxazin-1-yl.

“Cycloalkenyl” as used herein refers to a monocyclic, bicyclic, or amulticyclic cycloalkenyl ring system. Monocyclic ring systems are cyclichydrocarbon groups containing from 3 to 8 carbon atoms, where suchgroups are unsaturated (i.e., containing at least one annularcarbon-carbon double bond), but not aromatic. Examples of monocyclicring systems include cyclopentenyl and cyclohexenyl. Bicycliccycloalkenyl rings are bridged monocyclic rings or a fused bicyclicrings. Bridged monocyclic rings contain a monocyclic cycloalkenyl ringwhere two non-adjacent carbon atoms of the monocyclic ring are linked byan alkylene bridge of between one and three additional carbon atoms(i.e., a bridging group of the form —(CH₂)_(w)—, where w is 1, 2, or 3).Representative examples of bicyclic cycloalkenyls include, but are notlimited to, norbornenyl and bicyclo[2.2.2]oct-2-enyl. Fused bicycliccycloalkenyl ring systems contain a monocyclic cycloalkenyl ring fusedto either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl,a monocyclic heterocyclyl, or a monocyclic heteroaryl. The bridged orfused bicyclic cycloalkenyl is attached to the parent molecular moietythrough any carbon atom contained within the monocyclic cycloalkenylring. Cycloalkenyl groups are optionally substituted with one or twogroups which are independently oxo or thia. Multicyclic cycloalkenylrings contain a monocyclic cycloalkenyl ring (base ring) fused to either(i) one ring system selected from the group consisting of a bicyclicaryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicycliccycloalkenyl, and a bicyclic heterocyclyl; or (ii) two rings systemsindependently selected from the group consisting of a phenyl, a bicyclicaryl, a monocyclic or bicyclic heteroaryl, a monocyclic or bicycliccycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic orbicyclic heterocyclyl. The multicyclic cycloalkenyl is attached to theparent molecular moiety through any carbon atom contained within thebase ring. IN certain embodiments, multicyclic cycloalkenyl ringscontain a monocyclic cycloalkenyl ring (base ring) fused to either (i)one ring system selected from the group consisting of a bicyclic aryl, abicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, anda bicyclic heterocyclyl; or (ii) two rings systems independentlyselected from the group consisting of a phenyl, a monocyclic heteroaryl,a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclicheterocyclyl.

The term “halo” or “halogen” as used herein, means —Cl, —Br, —I or —F.

The term “haloalkyl” as used herein, means at least one halogen, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of haloalkyl include,but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl,pentafluoroethyl, and 2-chloro-3-fluoropentyl.

The term “heteroaryl,” as used herein, means a monocyclic, bicyclic, ora multicyclic heteroaryl ring system. The monocyclic heteroaryl can be a5 or 6 membered ring. The 5 membered ring consists of two double bondsand one, two, three or four nitrogen atoms and optionally one oxygen orsulfur atom. The 6 membered ring consists of three double bonds and one,two, three or four nitrogen atoms. The 5 or 6 membered heteroaryl isconnected to the parent molecular moiety through any carbon atom or anynitrogen atom contained within the heteroaryl. Representative examplesof monocyclic heteroaryl include, but are not limited to, furyl,imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl,thiadiazolyl, thiazolyl, thienyl, triazolyl, and triazinyl. The bicyclicheteroaryl consists of a monocyclic heteroaryl fused to a phenyl, amonocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclicheterocyclyl, or a monocyclic heteroaryl. The fused cycloalkyl orheterocyclyl portion of the bicyclic heteroaryl group is optionallysubstituted with one or two groups which are independently oxo or thia.When the bicyclic heteroaryl contains a fused cycloalkyl, cycloalkenyl,or heterocyclyl ring, then the bicyclic heteroaryl group is connected tothe parent molecular moiety through any carbon or nitrogen atomcontained within the monocyclic heteroaryl portion of the bicyclic ringsystem. When the bicyclic heteroaryl is a monocyclic heteroaryl fused toa phenyl ring or a monocyclic heteroaryl, then the bicyclic heteroarylgroup is connected to the parent molecular moiety through any carbonatom or nitrogen atom within the bicyclic ring system. Representativeexamples of bicyclic heteroaryl include, but are not limited to,benzimidazolyl, benzofuranyl, benzothienyl, benzoxadiazolyl,benzoxathiadiazolyl, benzothiazolyl, cinnolinyl,5,6-dihydroquinolin-2-yl, 5,6-dihydroisoquinolin-1 -yl, furopyridinyl,indazolyl, indolyl, isoquinolinyl, naphthyridinyl, quinolinyl, purinyl,5,6,7,8-tetrahydroquinolin-2-yl, 5,6,7,8-tetrahydroquinolin-3-yl,5,6,7,8-tetrahydroquinolin-4-yl, 5,6,7,8-tetrahydroisoquinolin-1-yl,thienopyridinyl, 4,5,6,7-tetrahydrobenzo[c][1,2,5]oxadiazolyl, and6,7-dihydrobenzo[c][1,2,5]oxadiazol-4(5H)-onyl. In certain embodiments,the fused bicyclic heteroaryl is a 5 or 6 membered monocyclic heteroarylring fused to either a phenyl ring, a 5 or 6 membered monocycliccycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 memberedmonocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl,wherein the fused cycloalkyl, cycloalkenyl, and heterocyclyl groups areoptionally substituted with one or two groups which are independentlyoxo or thia. The multicyclic heteroaryl group is a monocyclic heteroarylring (base ring) fused to either (i) one ring system selected from thegroup consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclicheterocyclyl, a bicyclic cycloalkenyl, and a bicyclic cycloalkyl; or(ii) two ring systems selected from the group consisting of a phenyl, abicyclic aryl, a monocyclic or bicyclic heteroaryl, a monocyclic orbicyclic heterocyclyl, a monocyclic or bicyclic cycloalkenyl, and amonocyclic or bicyclic cycloalkyl. The multicyclic heteroaryl group isconnected to the parent molecular moiety through any carbon atom ornitrogen atom contained within the base ring. In certain embodiments,multicyclic heteroaryl groups are a monocyclic heteroaryl ring (basering) fused to either (i) one ring system selected from the groupconsisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclicheterocyclyl, a bicyclic cycloalkenyl, and a bicyclic cycloalkyl; or(ii) two ring systems selected from the group consisting of a phenyl, amonocyclic heteroaryl, a monocyclic heterocyclyl, a monocycliccycloalkenyl, and a monocyclic cycloalkyl. Examples of multicyclicheteroaryls include, but are not limited to5H-[1,2,4]triazino[5,6-b]indol-5-yl,2,3,4,9-tetrahydro-1H-carbazol-9-yl, 9H-pyrido[3,4-b]indol-9-yl,9H-carbazol-9-yl, and acridin-9-yl.

The term “heteroarylalkyl” and “-alkylheteroaryl” as used herein, meansa heteroaryl, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofheteroarylalkyl include, but are not limited to, fur-3-ylmethyl,1H-imidazol-2-ylmethyl, 1H-imidazol-4-ylmethyl, 1-(pyridin-4-yl)ethyl,pyridin-3-ylmethyl, pyridin-4-ylmethyl, pyrimidin-5-ylmethyl,2-(pyrimidin-2-yl)propyl, thien-2-ylmethyl, and thien-3-ylmethyl.

The term “heterocyclyl” as used herein, means a monocyclic, bicyclic, ormulticyclic heterocycle. The monocyclic heterocycle is a 3, 4, 5, 6 or 7membered ring containing at least one heteroatom independently selectedfrom the group consisting of O, N, and S where the ring is saturated orunsaturated, but not aromatic. The 3 or 4 membered ring contains 1heteroatom selected from the group consisting of O, N and S. The 5membered ring can contain zero or one double bond and one, two or threeheteroatoms selected from the group consisting of O, N and S. The 6 or 7membered ring contains zero, one or two double bonds and one, two orthree heteroatoms selected from the group consisting of O, N and S. Themonocyclic heterocycle is connected to the parent molecular moietythrough any carbon atom or any nitrogen atom contained within themonocyclic heterocycle. Representative examples of monocyclicheterocycle include, but are not limited to, azetidinyl, azepanyl,aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl,1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl,isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl,oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl,piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl,pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl,thiadiazolidinyl, thiazolinyl, thiazolidinyl,thiomorpholinyl,1,1-dioxidothiomorpholinyl(thiomorpholine sulfone),thiopyranyl, and trithianyl. The bicyclic heterocycle is a monocyclicheterocycle fused to either a phenyl, a monocyclic cycloalkyl, amonocyclic cycloalkenyl, a monocyclic heterocycle, or a monocyclicheteroaryl. The bicyclic heterocycle is connected to the parentmolecular moiety through any carbon atom or any nitrogen atom containedwithin the monocyclic heterocycle portion of the bicyclic ring system.Representative examples of bicyclic heterocyclyls include, but are notlimited to, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl,indolin-1-yl, indolin-2-yl, indolin-3-yl, 2,3-dihydrobenzathien-2-yl,decahydroquinolinyl, decahydroisoquinolinyl, octahydro-1H-indolyl, andoctahydrobenzofuranyl. Heterocyclyl groups are optionally substitutedwith one or two groups which are independently oxo or thia. In certainembodiments, the bicyclic heterocyclyl is a 5 or 6 membered monocyclicheterocyclyl ring fused to phenyl ring, a 5 or 6 membered monocycliccycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 memberedmonocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl,wherein the bicyclic heterocyclyl is optionally substituted by one ortwo groups which are independently oxo or thia. Multicyclic heterocyclylring systems are a monocyclic heterocyclyl ring (base ring) fused toeither (i) one ring system selected from the group consisting of abicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicycliccycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ringssystems independently selected from the group consisting of a phenyl, abicyclic aryl, a monocyclic or bicyclic heteroaryl, a monocyclic orbicyclic cycloalkyl, a monocyclic or bicyclic cycloalkenyl, and amonocyclic or bicyclic heterocyclyl. The multicyclic heterocyclyl isattached to the parent molecular moiety through any carbon atom ornitrogen atom contained within the base ring. In certain embodiments,multicyclic heterocyclyl ring systems are a monocyclic heterocyclyl ring(base ring) fused to either (i) one ring system selected from the groupconsisting of a bicyclic aryl, a bicyclic heteroaryl, a bicycliccycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or(ii) two other rings systems independently selected from the groupconsisting of a phenyl, a monocyclic heteroaryl, a monocycliccycloalkyl, a monocyclic cycloalkenyl, and a monocyclic heterocyclyl.Examples of multicyclic heterocyclyl groups include, but are not limitedto 10H-phenothiazin-10-yl, 9,10-dihydroacridin-9-yl,9,10-dihydroacridin-10-yl, 10H-phenoxazin-10-yl,10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl,1,2,3,4-tetrahydropyrido[4,3-g]isoquinolin-2-yl,12H-benzo[b]phenoxazin-12-yl, and dodecahydro-1H-carbazol-9-yl.

The term “nitro” as used herein, means a —NO₂ group.

The term “oxo” as used herein means a ═O group.

The term “saturated” as used herein means the referenced chemicalstructure does not contain any multiple carbon-carbon bonds. Forexample, a saturated cycloalkyl group as defined herein includescyclohexyl, cyclopropyl, and the like.

The term “thia” as used herein means a ═S group.

The term “unsaturated” as used herein means the referenced chemicalstructure contains at least one multiple carbon-carbon bond, but is notaromatic. For example, a unsaturated cycloalkyl group as defined hereinincludes cyclohexenyl, cyclopentenyl, cyclohexadienyl, and the like.

As used herein, the phrase “pharmaceutically acceptable salt” refers toboth pharmaceutically acceptable acid and base addition salts andsolvates. Such pharmaceutically acceptable salts include salts of acidssuch as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic,formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric,tartaric, maleic, hydroiodic, alkanoic such as acetic,HOOC—(CH₂)_(n)—COOH where n is 0-4, and the like. Non-toxicpharmaceutical base addition salts include salts of bases such assodium, potassium, calcium, ammonium, and the like. Those skilled in theart will recognize a wide variety of non-toxic pharmaceuticallyacceptable addition salts.

EXAMPLES

Unless otherwise stated, all chemicals were purchased from commercialsuppliers and used without further purification. Inhibitors weresynthesized through several different routes, as represented in Schemes1-8.

Example 1 Methyl2-(4-{[3-(adamantan-1-yl)-4-methoxyphenyl]sulfanyl}phenyl)-acetate (a)1-(5-iodo-2-methoxyphenyl)adamantane

1-(5-iodo-2-methoxyphenyl)adamantane was prepared according to modifiedprocedures of Kalvinsh et al. (WO2008086942A2) and Sarshar(WO2005108338A1), both incorporated herein by reference. Briefly,sulfuric acid (1 mmol) was slowly added to a solution of 1-adamantanol(1 mmol) and 4-iodoanisole (1.5 mmol) in dichloromethane (20 mL). Themixture was stirred during 48 hours and then poured in water (50 mL). Asolution of saturated sodium bicarbonate was added until pH=8. Theorganic layer was extracted with dichloromethane (3×100 mL) and washedwith a 10% sodium sulfite aqueous solution (3×50 mL). After evaporationof volatile, the organic crude was purified by chromatography(cyclohexane/dichloromethane): (95/5) to (75/25) to afford a whitepowder (65%). mp=135° C. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.75 (s,6H), 2.04 (s, 10H), 3.79 (s, 3H), 6.62 (d, J=9.16 Hz, 1H), 7.40-7.50 (m,2H).

(b) methyl 2-(4-sulfanylphenyl)acetate

To a solution of 2-(4-sulfanylphenyl)acetic acid (980 mg, 5.8 mmol) inmethanol (20 mL), was added conc. sulfuric acid (0.03 mL). The solutionwas stirred to reflux for 3 hours and then at r.t. overnight. Afterevaporation of the volatiles, conc. NaHCO₃ was added until pH=8 and thesolution was extracted with ethyl acetate (3×50 mL). The organic layerswere combined, dried over CaSO4 and evaporated. The crude was purifiedby column chromatography using the following gradient system,(cyclohexane/ethyl acetate):(93/7) to (60/40), to afford a colorless oil(920 mg, 88%). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.43 (s, 1H), 3.56(s, 2H), 3.68 (s, 3H), 7.14 (d, J=8.16 Hz, 2H), 7.23 (d, J=8.16 Hz, 2H).

(c) methyl2-(4-{[3-(adamantan-1-yl)-4-methoxyphenyl]sulfanyl}phenyl)acetate

To a mixture of methyl 2-(4-sulfanylphenyl)acetate (130 mg, 0.71 mmol, 1eq.) and 2-(1-adamantyl)-4-iodoanisole (262 mg, 0.71 mmol, 1 eq.) indioxane (5 mL) and butanol (5 mL), were added the borohydride, polymersupported (650 mg, 2.5-5 mmol/g, 3 eq.) and (bpy)₂NiBr₂ (70 mg, 0.2eq.). The mixture was heated to 145° C. under an atmosphere of nitrogen.The polymer beads were removed by filtration, and the mixture wasconcentrated to dryness before purification by flash chromatographyusing the following gradient system, (cyclohexane/dichloromethane):(20/80) to (0/100) afforded a colorless oil (120 mg, 14%) as a mixtureof methyl2-(4-{[3-(adamantan-1-yl)-4-methoxyphenyl]sulfanyl}phenyl)acetate andbutyl 2-(4-{[3-(adamantan-1-yl)-4-methoxyphenyl]sulfanyl}phenyl)acetate(12%). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.75 (s, 6H), 2.06 (s, 9H),3.56 (s, 2H), 3.68 (s, 3H), 3.84 (s, 3H), 6.85 (d, J=8.41 Hz, 1H),7.05-7.18 (m, 4H), 7.28 (d, J=8.41 Hz, 1H), 7.35 (br. s., 1H).

Example 2 Butyl2-(4-{[3-(adamantan-1-yl)-4-methoxyphenyl]sulfanyl}phenyl)-acetate

butyl 2-(4-{[3-(adamantan-1-yl)-4-methoxyphenyl]sulfanyl}phenyl)acetatewas obtained in example 1(c). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.90(t, J=7.09 Hz, 3H), 1.27-1.39 (m, 2H), 1.52-1.56 (m, 2H), 2.06 (s, 9H),3.56 (s, 2H), 3.84 (s, 3H), 4.07 (t, J=6.59 Hz, 2H), 6.85 (d, J=8.41 Hz,1H), 7.05-7.18 (m, 4H), 7.28 (d, J=8.41 Hz, 1H), 7.35 (br. s., 1H).

Example 32-(4-{[3-(adamantan-1-yl)-4-methoxyphenyl]sulfanyl}phenyl)acetic acid

To a solution of the mixture of methyl2(4-{[3-(adamantan-1-yl)-4-methoxyphenyl]sulfanyl}phenyl)acetate andbutyl 2-(4-{[3-(adamantan-1-yl)-4-methoxyphenyl]sulfanyl}phenyl) (60 mg,0.118 mmol) in THF (6 mL), was added 440 μL of a 1N solution of lithiumhydroxide in water. The reaction was stirred at room temperatureovernight. After acidification with 1N HCl until pH=1, the crude wasextracted with DCM. The organic layers were combined, dried over Ca₂SO₄and concentrated to afford a white solid, without any furtherpurification (57 mg, 99%). mp=132-134° C. ¹H NMR (400 MHz, CHLOROFORM-d)δ ppm 1.75 (s, 6H), 2.06 (s, 9H), 3.58 (s, 2H), 3.84 (s, 3H), 6.85 (d,J=8.41 Hz, 1H), 7.05-7.18 (m, 4H), 7.29 (dd, J=8.41, 1.88 Hz, 1H), 7.35(d, J=1.88 Hz, 1H). HRMS (TOF MS ES−) for C25H27O3S⁻ (M−H)⁻ calcd.407.1681, found 407.1695.

Example 4 Methyl2-(3-{[3-(adamantan-1-yl)-4-methoxyphenyl]sulfanyl}phenyl)-acetate (a)methyl 2-(3-sulfanylphenyl)acetate

Methyl 2-(3-sulfanylphenyl)acetate was prepared according to example1(b) starting from 1.16 g of 2-(3-sulfanylphenyl)acetic acid. Acolorless oil was obtained (1.2 g, 95%), ¹H NMR (400 MHz, CHLOROFORM-d)δ ppm 3.45 (s, 1H), 3.56 (s, 2H), 3.69 (s, 3H), 7.06 (d, J=5.77 Hz, 1H),7.15-7.22 (m, 3H).

(b) Methyl2-(3-{[3-(adamantan-1-yl)-4-methoxyphenyl]sulfanyl}phenyl)acetate

Methyl 2-(3-{[3-(adamantan-1-yl)-4-methoxyphenyl]sulfanyl}phenyl)acetatewas prepared according to example 1(c) starting from 180 mg of methyl2-(3-sulfanylphenyl)acetate. A colorless oil (205 mg, 50%) was obtainedas a mixture of methyl2-(3-{[3-(adamantan-1-yl)-4-methoxyphenyl]sulfanyl}phenyl)acetate andbutyl 2-(3-{[3-(adamantan-1-yl)-4-methoxyphenyl]sulfanyl}phenyl)acetate(25%). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.76 (s, 6H), 2.06 (s, 9H),3.55 (s, 2H), 3.67 (s, 3H), 3.85 (s, 3H), 6.86 (d, J=8.28 Hz, 1H),6.98-7.07 (m, 2H), 7.09 (s, 1H), 7.14-7.22 (m, 1H), 7.30 (d, J=8.41 Hz,1H), 7.35 (s, 1H).

Example 5 Butyl2-(3-{[3-(adamantan-1-yl)-4-methoxyphenyl]sulfanyl}phenyl)acetate

Butyl 2-(3-{[3-(adamantan-1-yl)-4-methoxyphenyl]sulfanyl}phenyl)acetatewas obtained in example 4. ¹H NMR (400 MHz, CHLOROFORM-d) 67 ppm 0.91(t, J=7.09 Hz, 3H), 1.29-1.38 (m, 2H), 1.55-1.62 (m, 2H), 1.76 (s, 6H),2.06 (s, 9H), 3.55 (s, 2H), 3.85 (s, 3H), 4.07 (t, J=6.71 Hz, 2H), 6.86(d, J=8.28 Hz, 1H), 6.98-7.07 (m, 2H), 7.09 (s, 1H), 7.14-7.22 (m, 1H),7.30 (d, J=8.41 Hz, 1H), 7.35 (s, 1H).

Example 62-(3-{[3-(Adamantan-1-yl)-4-methoxyphenyl]sulfanyl}phenyl)acetic acid

2-(3-{[3-(adamantan-1-yl)-4-methoxyphenyl]sulfanyl}phenyl)acetic acidwas prepared according to example 3 using 50 mg of of the mixture ofmethyl 2-(3-{[3-(adamantan-1-yl)-4-methoxyphenyl]sulfanyl}phenyl)acetateand butyl2-(3-{[3-(adamantan-1-yl)-4-methoxyphenyl]sulfanyl}phenyl)acetate. Awhite solid was obtained (45 mg, 94%). mp=134° C. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.75 (s, 6H) 1.96-2.02-2.10 (m, 9H), 3.56 (s, 2H),3.84 (m, 3H), 6.85 (d, J=8.41 Hz, 1H), 6.98-7.07 (m, 2H) 7.09 (s, 1H)7.15-7.22 (m, 1H) 7.29 (dd, J=8.41, 2.26 Hz, 1H) 7.35 (d, J=2.26 Hz,1H). HRMS (TOF MS ES−) for C25H27O3S− (M−H)− calcd. 407.1681, found407.1706.

Example 7 Methyl2-{4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)sulfanyl]phenyl}acetate(a) 6-iodo-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene

6-iodo-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene was preparedaccording to Christie, Victoria B. et al (Organic & BiomolecularChemistry, 6(19), 3497-3507; 2008).

(b) methyl2-{4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)sulfanyl]phenyl}acetate

Methyl2-{4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)sulfanyl]phenyl}acetatewas prepared according to example 1(c) starting from 305 mg of6-iodo-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene. A colorlessoil was obtained (225 mg, 60%) as a mixture of methyl2-{4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)sulfanyl]phenyl}acetateand butyl2-{4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)sulfanyl]phenyl}acetate(25%). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.26 (s, 6H), 1.24 (s, 6H),1.67 (s, 4H), 3.59 (s, 2H), 3.69 (s, 3H), 7.09 (dd, J=8.28, 1.51 Hz,1H), 7.16-7.21 (m, 2H), 7.22-7.25 (m, 3H), 7.35 (d, J=1.88 Hz, 1H).

Example 8 Butyl2-{4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)sulfanyl]phenyl}acetate

Butyl2-{4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)sulfanyl]phenyl}acetatewas obtained in example 7(b). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.92(t, J=7.09 Hz, 3H), 1.26 (s, 6H), 1.24 (s, 6H), 1.36-1.42 (m, 2H),1.56-1.63 (m, 2H), 1.67 (s, 4H), 3.69 (s, 3H), 4.08 (t, J=6.71 Hz, 2H),7.09 (dd, J=8.28, 1.51 Hz, 1H), 7.16-7.21 (m, 2H), 7.22-7.25 (m, 3H)),7.35 (d, J=1.88 Hz, 1H).

Example 92-{4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)sulfanyl]phenyl}aceticacid

2-{4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)sulfanyl]phenyl)}aceticacid was prepared according to example 3 using 50 mg of (b) methyl2-{4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)sulfanyl]phenyl}acetate.A white solid was obtained (43 mg, 99%). mp=87° C. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.24 (s, 6H) 1.27 (s, 6H) 1.67 (s, 4H) 3.60 (s, 2H)7.07-7.12 (m, 1H) 7.15-7.25 (m, 5H) 7.33-7.37 (m, 1H). HRMS (TOF MS ES−)for [(C22H26O2S)₂-1]⁻ (M−H)⁻ calcd. 707.3229, found 707.3204.

Example 10 Methyl2-{3-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)sulfanyl]phenyl}acetate

Methyl2-{3-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)sulfanyl]phenyl}acetatewas prepared according to example 1(c) starting from 305 mg of6-iodo-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene. A colorlessoil (210 mg, 55%) was obtained as a mixture of methyl2-{3-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)sulfanyl]phenyl}and butyl2-{3-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)sulfanyl]phenyl}(25%). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.27 (s, 6H), 1.24 (s, 6H),1.68 (s, 4H), 3.57 (s, 2H), 3.67 (s, 3H), 7.07-7.14 (m, 2H), 7.14-7.18(m, 1H), 7.23 (m, 3H), 7.34 (d, J=1.88 Hz, 1H).

Example 11 Butyl2-{3-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)sulfanyl]phenyl}acetate

Butyl2-{3-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)sulfanyl]phenyl}acetatewas obtained in example 10. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.94(t, J=7.09 Hz, 3H), 1.27 (s, 6H), 1.24 (s, 6H), 1.32-1.41 (m, 2H),1.52-1.59 (m, 2H), 1.68 (s, 4H), 3.57 (s, 2H), 4.07 (t, J=6.71 Hz, 2H),7.07-7.14 (m, 2H), 7.14-7.18 (m, 1H), 7.23 (m, 3H), 7.34 (d, J=1.88 Hz,1H).

Example 122-{3-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)sulfanyl]phenyl}aceticacid

2-{3-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)sulfanyl]phenyl}aceticacid was prepared according to example 3 using 50 mg of the mixture ofmethyl2-{3-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)sulfanyl]phenyl}acetateand butyl2-{3-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)sulfanyl]phenyl}acetate.A colorless oil was obtained (43 mg, 99%). ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.22 (s, 6H), 1.27 (s, 6H), 1.67 (s, 4H), 3.58 (s,2H), 7.07-7.13 (m, 2H), 7.14-7.19 (m, 1H), 7.19-7.24 (m, 3H), 7.34 (d,J=1.88 Hz, 1H). HRMS (TOF MS ES−) for C22H25O2S⁻ (M−H)⁻ calcd. 353.1575,found 407.1591.

Example 13 Methyl2-(4-{[3-(adamantan-1yl)-4-methoxybenzene]sulfonyl}phenyl)-acetate

To a solution of mixture obtained in example 1(c) (110 mg, 0.26 mmol, 1eq.) in THF (7 mL), was added a solution of oxone (475 mg, 0.775 mmol, 3eq.) in water (4 mL). The reaction was stirred overnight at roomtemperature. Water (10 mL) was added and the mixture was extracted withdichloromethane (3×50 mL). After drying over Ca₂SO₄ and evaporation, thecrude was purified by flash chromatography(cyclohexane/dichloromethane): (80/20) to (0/100). A white powder wasobtained (80 mg, 70%) as a mixture of methyl2-(4-{[3-(adamantan-1-yl)-4-methoxybenzene]sulfonyl}phenyl)acetate andbutyl 2-(4-{[3-(adamantan-1-yl)-4-methoxybenzene]sulfonyl}phenyl)acetate(10%). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.76 (s, 6H), 2.05 (s, 9H),3.67 (s, 2H), 3.69 (s, 3H), 3.87 (s, 3H), 6.91 (d, J=9.16 Hz, 1H), 7.40(d, J=8.16 Hz, 2H), 7.73-7.80 (m, 2H), 7.88 (d, J=8.28 Hz, 2H).

Example 14 Butyl2-(4-{[3-(adamantan-1-yl)-4-methoxybenzene]sulfonyl}phenyl)acetate

Butyl 2-(4-{[3-(adamantan-1-yl)-4-methoxybenzene]sulfonyl}phenyl)acetatewas obtained from example 13. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.89(t, J=7.09 Hz, 3H), 1.28-1.37 (m, 2H), 1.51-1.60 (m, 2H), 1.76 (s, 6H),2.05 (s, 9H), 3.67 (s, 2H), 3.87 (s, 3H), 4.09 (t, J=6.59 Hz, 2H), 6.91(d, J=9.16 Hz, 1H), 7.40 (d, J=8.16 Hz, 2H), 7.73-7.80 (m, 2H), 7.88 (d,J=8.28 Hz, 2H).

Example 152-(4-{[3-(adamantan-1-yl)-4-methoxybenzene]sulfonyl}phenyl)acetic acid

2-(4-{[3-(adamantan-1-yl)-4-methoxybenzene]sulfonyl}phenyl)acetic acidwas prepared according to example 3 using 50 mg of methyl2-(4-{[3-(adamantan-1-yl)-4-methoxybenzene]sulfonyl}phenyl)acetate. Awhite solid is obtained (35 mg, 73%). mp=212° C. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.76 (s, 6H), 2.05 (m, 10H), 3.70 (s, 2H), 3.87 (s,3H), 6.90 (d, J=9.29 Hz, 1H), 7.39 (m, J=8.28 Hz, 2H), 7.70-7.81 (m,2H), 7.88 (m, J=8.28 Hz, 2H). HRMS (TOF MS ES−) for C22H25O2S⁻ (M−H)⁻calcd. 353.1575, found 407.1591. HRMS (TOF MS ES−) for [(C25H28O5S)₂-1]⁻(M−H)⁻ calcd. 879.3237, found 879.3265.

Example 16 Methyl2-(3-{[3-(adamantan-1-yl)-4-methoxybenzene]sulfonyl}phenyl)-acetate

Methyl2-(3-{[3-(adamantan-1-yl)-4-methoxybenzene]sulfonyl}phenyl)acetate wasprepared according to example 13 using 90 mg of mixture obtained inexample 4(b). A thick oil was obtained (50 mg, 50%) as a mixture ofmethyl2-(3-{[3-(adamantan-1-yl)-4-methoxybenzene]sulfonyl}phenyl)acetate andthe butyl2-(3-{[3-(adamantan-1-yl)-4-methoxybenzene]sulfonyl}phenyl)acetate(25%). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.76 (s, 6H), 2.05 (s, 9H),3.68 (s, 2H), 3.69 (s, 3H), 3.87 (s, 3H), 6.88-6.94 (m, 1H), 7.42-7.49(m, 2H), 7.74-7.79 (m, 2H), 7.82 (dt, J=6.59, 2.04 Hz, 1H), 7.85 (br.s,1H).

Example 17 Butyl2-(3-{[3-(adamantan-1-yl)-4-methoxybenzene]sulfonyl}phenyl)acetate

Butyl 2-(3-{[3-(adamantan-1-yl)-4-methoxybenzene]sulfonyl}phenyl)acetatewas obtained from example 16. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.90(t, J=7.09 Hz, 3H), 1.26-1.38 (m, 2H), 1.55-1.62 (m, 2H), 1.76 (s, 6H),2.05 (s, 9H), 3.68 (s, 2H), 3.87 (s, 3H), 4.09 (t, J=6.71 Hz, 2H),6.88-6.94 (m, 1H), 7.42-7.49 (m, 2H), 7.74-7.79 (m, 2H), 7.82 (dt,J=6.59, 2.04 Hz, 1H), 7.85 (br.s, 1H).

Example 182-(3-{[3-(adamantan-1-yl)-4-methoxybenzene]sulfonyl}phenyl)acetic acid

2-(3-{[3-(adamantan-1-yl)-4-methoxybenzene]sulfonyl}phenyl)acetic acidwas prepared according to example 3 using 50 mg of the mixture of methyl2-(3-{[3-(adamantan-1-yl)-4-methoxybenzene]sulfonyl}phenyl)acetate andbutyl2-(3-{[3-(adamantan-1-yl)-4-methoxybenzene]sulfonyl}phenyl)acetate. Awhite solid is obtained (45 mg, 95%). mp=174° C. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.75 (s, 6H), 2.04 (s, 9H), 3.71 (s, 2H), 3.86 (s,3H), 6.91 (d, J=9.29 Hz, 1H), 7.46 (m, 2H), 7.71-7.79 (m, 2H), 7.79-7.90(m, 2H). HRMS (TOF MS ES−) for C25H27O5S− (M−H)− calcd. 439.1579, found439.1600.

Example 19 Methyl2-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-sulfonyl)phenyl]acetate

Methyl2-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-sulfonyl)phenyl]acetatewas prepared according to example 13 using 105 mg of the mixtureobtained in example 7(b). An off-white solid was obtained (61 mg, 54%)as a mixture of methyl2-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-sulfonyl)phenyl]acetateand butyl2-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-sulfonyl)phenyl]acetate(5%). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (s, 6H), 1.26 (s, 6H),1.68 (s, 4H), 3.67 (s, 2H), 3.69 (s, 3H), 7.40 (m, 3H), 7.58 (dd,J=8.41, 2.01 Hz, 1H), 7.86-7.93 (m, 3H).

Example 20 Butyl2-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-sulfonyl)phenyl]acetate

Butyl2-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-sulfonyl)phenyl]acetatewas obtained in example 19. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.88(t, J=7.09 Hz, 3H), 1.29 (s, 6H), 1.26 (s, 6H), 1.37-1.43 (m, 2H),1.56-1.63 (m, 2H), 1.68 (s, 4H), 3.67 (s, 2H), 4.09 (t, J=6.71 Hz, 2H),7.40 (m, 3H), 7.58 (dd, J=8.41, 2.01 Hz, 1H), 7.86-7.93 (m, 3H).

Example 212-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-sulfonyl)phenyl]aceticacid

2-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-sulfonyl)phenyl]aceticacid was prepared according to example 3 using 45 mg of the mixture ofmethyl2-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-sulfonyl)phenyl]acetateand butyl2-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-sulfonyl)phenyl]acetate.A white solid is obtained (31 mg, 72%). mp=214° C. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.29 (s, 6H), 1.25 (s, 6H), 1.68 (s, 4H), 3.70 (s,2H), 7.40 (m, 3H), 7.58 (dd, J=8.41, 2.01 Hz, 1H), 7.87-7.93 (m, 3H).HRMS (TOF MS ES−) for [(C22H26O4S)₂-1]- (M−H)− calcd. 771.3025, found771.3063.

Example 22 Methyl2-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-sulfonyl)phenyl]acetate

Methyl2-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-sulfonyl)phenyl]acetatewas prepared according to example 13 using 90 mg of the mixture obtainedin example 10. A thick oil was obtained (50 mg, 51%). ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.29 (s, 6H) 1.26 (s, 6H) 1.68 (s, 4H) 3.69 (s, 5H)7.40 (d, J=8.41 Hz, 1H) 7.43-7.52 (m, 2H) 7.59 (dd, J=8.41, 1.88 Hz, 1H)7.83 (dt, J=7.00, 1.65 Hz, 1H) 7.88 (s, 1H) 7.90 (d, J=2.01 Hz, 1H).

Example 232-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-sulfonyl)phenyl]-aceticacid

2-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-sulfonyl)phenyl]aceticacid was prepared according to example 3 using 45 mg of methyl2-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-sulfonyl)phenyl]acetate.A white solid is obtained (41 mg, 95%). mp=75° C. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.25 (s, 6H), 1.27 (s, 6H), 1.67 (s, 4H), 3.72 (s,2H), 7.39 (d, J=8.41 Hz, 1H), 7.43-7.52 (m, 2H), 7.56-7.63 (m, 1H), 7.84(d, J=6.27 Hz, 1H), 7.89 (s, 2H). HRMS (TOF MS ES−) for C22H25O4S−(M−H)− calcd. 385.1474, found 385.1494.

Example 24 Ethyl3-{4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)sulfanyl]phenyl}propanoate5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-naphthalene-2-disulfide

5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-naphthalene-2-disulfide wasprepared according to a procedure described by Boiteau et al.(WO2014016507A1). mp=83-85° C. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.24(s, 6H), 1.21 (s, 6H,) 1.65 (s, 4H), 7.23 (d, J=8.28 Hz, 1H), 7.28 (dd,J=8.28, 1.88 Hz, 1H), 7.41 (d, J=1.88 Hz, 1H).

(a) Ethyl3-{4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)sulfanyl]phenyl}propanoate

Ethyl3-{4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)sulfanyl]phenyl}propanoatewas prepared according to the method described by Fukuzawa et al.(Synlett 2006, 13, 2145-47).5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-naphthalene-2-disulfide (100 mg,0.228 mmol, 0.5 eq.), PdCl₂(dppf) (17 mg, 0.023 mmol, 0.05 eq.), andzinc (36 mg, 0.547 mmol, 1.2 eq.) were placed in a flask and then asolution of ethyl 3-(4-bromophenyl)propanoate (115 mg, 0.456 mmol, 1eq.) in THF (3 mL) was added. The mixture was refluxed for 24 h anddiluted with Et₂O (30 mL) after cooling. The precipitate was removed byfiltration and the filtrate was washed with brine and dried over Ca₂SO₄.After concentration of the organic layer, the crude was concentrated andgrossly purified by chromatography over silica gel(cyclohexane/dichloromethane): (95/5) to (55/45). A mixture of the titlecompound and ethyl 3-(4-bromophenyl)propanoate (30%) was obtained (125mg). It was used in the next step without any further purification.

Example 25 Ethyl3-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-sulfonyl)phenyl]propanoate

Ethyl3-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-sulfonyl)phenyl]propanoatewas prepared according to example 13 using 125 mg of mixture obtained inexample 24 (b). A white solid was obtained (82 mg, 87%). mp=105-106° C.¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.19 (t, J=7.11 Hz, 3H), 1.28 (s,6H), 1.25 (s, 6H), 1.68 (s, 4H), 2.62 (t, J=7.53 Hz, 2H), 2.99 (t,J=7.53 Hz, 2H), 4.10 (q, J=7.11 Hz, 2H), 7.33 (m, J=8.16 Hz, 2H), 7.39(d, J=8.41 Hz, 1H), 7.58 (dd, J=8.41, 1.51 Hz, 1H), 7.85 (m, J=8.16 Hz,2H), 7.88-7.92 (m, 1H).

Example 263-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-sulfonyl)phenyl]propanoicacid

3-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-sulfonyl)phenyl]propanoicacid was prepared according to example 3 starting from 66 mg of ethyl3-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-sulfonyl)phenyl]propanoate.A white solid is obtained (53 mg, 85%). mp=211° C. ¹H NMR (400 MHz,METHANOL-d₄) δ ppm 1.30 (s, 6H), 1.32 (s, 6H), 1.75 (s, 4H), 2.65 (t,H=7.59 Hz, 2H), 3.01 (t, J=7.59 Hz, 2H), 7.48 (m, J=8.41 Hz, 2H), 7.56(d, J=8.41 Hz, 1H), 7.65 (dd, J=8.41, 2.01 Hz, 1H), 7.87 (m, J=8.41 Hz,2H), 7.90 (d, J=2.01 Hz, 1H). HRMS (TOF MS ES−) for C23H27O4S− (M−H)−calcd. 399.1630, found 399.1658.

Example 27 Ethyl3-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)phenyl]propanoate

Ethyl3-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)phenyl]propanoatewas prepared according to the procedure described by Suzuki and co.(Synth. Com. 1981, 513-19). To a solution of6-bromo-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (110 mg, 0.41mmol, 1 eq.) in degassed toluene (1 mL), a solution of4-(2-ethoxycarbonyl)phenylboronic acid (100 mg, 0.45 mmol, 1.1 eq,) indegassed ethanol (0.2 mL) and a solution of K₂CO₃ (113 mg, 0.82 mmol, 2eq.) in degassed water (0.4 mL) were successively added. Then Pd(PPh₃)₄(14 mg, 0.0123 mmol, 0.03 eq.) was added and the resulting mixture washeated to reflux for 3 h 30. Water was added and the mixture wasextracted with dichloromethane. The resulting organic layers were driedover brine and Ca₂SO₄ and then concentrated. The crude was purified byflash chromatography, (cyclohexane/dichloromethane): (65/35) to (35/65)to afford a thick yellow oil (80 mg, 60%), ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.24 (t, J=7.15 Hz, 2H), 1.31 (s, 6H), 1.33 (s, 6H),1.71 (s, 4H), 2.65 (t, J=7.72 Hz, 2H), 2.98 (t, J=7.72 Hz, 2H), 4.14 (q,J=7.15 Hz, 2H), 7.25 (d, J=7.15 Hz, 2H), 7.30-7.39 (m, 2H), 7.45-7.53(m, 3H).

Example 283-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)phenyl]propanoicacid

3-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)phenyl]propanoicacid was prepared according to example 3 starting from 60 mg of ethyl3-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)phenyl]propanoate.A white solid is obtained (50 mg, 88%). mp=196° C. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.32 (s, 6H), 1.33 (s, 6H) 1.65-1.77 (m, 4H), 2.73(t, J=6.90 Hz, 2H), 3.01 (t, J=6.90 Hz, 2H), 7.26-7.30 (m, 2H),7.30-7.40 (m, 2H), 7.46-7.54 (m, 3H). HRMS (TOF MS ES−) for C23H27O2−(M−H)− calcd. 335.2011 found 335.2010.

Example 29 Ethyl3-{4-[3-(adatnantan-1-yl)-4-methoxyphenyl]phenyl}propanoate

Ethyl 3-{4-[3-(adamantan-1-yl)-4-methoxyphenyl]phenyl}propanoate wasprepared according to example 27 starting from 600 mg of2-adamantyl-4-iodoanisole. A white solid was obtained (275 mg, 40%),mp=124° C. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J=7.03 Hz, 3H),1.78 (s, 6H), 2.08 (s, 3H), 2.14 (s, 6H), 2.65 (t, J=7.78 Hz, 2H), 2.98(t, J=7.78 Hz, 2H), 3.86 (s, 3H), 4.14 (q, J=7.03 Hz, 2H), 6.93 (d,J=8.30 Hz, 1H), 7.20-7.28 (m, 2H), 7.38 (d, J=8.30 Hz, 1H), 7.43 (s,1H), 7.48 (d, J=7.78 Hz, 2H).

Example 30 3-{4-[3-(adamantan-1-yl)-4-methoxyphenyl]phenyl}propanoicacid

3-{4-[3-(adamantan-1-yl)-4-methoxyphenyl]phenyl}propanoic acid wasprepared according to example 3 starting from 275 mg of ethyl3-{4-[3-(adatnantan-1-yl)-4-methoxyphenyl]phenyl}propanoate. A whitesolid is obtained (200 mg, 75%). mp=252-253° C. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.78 (s, 6H), 2.08 (s, 3H), 2.14 (s, 6H), 2.72 (t,J=7.76 Hz, 2H), 3.00 (t, J=7.76 Hz, 2H), 3.87 (s, 3H), 6.93 (d, J=8.41Hz, 1H), 7.24 (s, 2H), 7.38 (dd, J=8.28, 2.13 Hz, 1H), 7.43 (d, J=2.13Hz, 1H), 7.49 (d, J=8.41 Hz, 2H). HRMS (TOF MS ES+) for C₂₆H₃₁O₃ ⁺ (MH+)calcd. 391.2273, found 391.2291.

Example 31 3-{4-[3-(adamantan-1-yl)-4-hydroxyphenyl]phenyl}propanoicacid

3-{4-[3-(adamantan-1-yl)-4-methoxyphenyl]phenyl}propanoic acid (270 mg,0.7 mmol, 1 eq.) was suspended in dichloromethane (10 mL) and a 1Msolution of BBr₃ in dichloromethane (2.8 mL) was slowly added at −78° C.The mixture was stirred at −78° C. for 30 minutes and then slowly warmedup to 0° C. and kept at this temperature for 2 hours. Water was added(10 mL) at 0° C. and the mixture was extracted with dichloromethane(3×50 mL). The resulting organic layers were dried over brine and Ca₂SO₄and then concentrated to afford a brown solid without any furtherpurification. mp=212-215° C. ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 1.85(br. s., 6H) 2.09 (br. s., 3H) 2.24 (br. s., 6H) 2.65 (br. s., 2H) 2.95(br. s., 2H) 6.79 (d, J=7.78 Hz, 1H) 7.15-7.31 (m, 3H) 7.37 (br. s., 1H)7.41-7.55 (m, 2H). HRMS (TOF MS ES+) for C₂₅H₂₉O₃ ⁺ (MH+) calcd.377.2117, found 377.2107.

Example 32 Benzyl(2E)-3-{4-[3-(adamantan-1-yl)-4-methoxyphenyl]phenyl}prop-2-enoate (a)E)-Benzyl 3(4-bromophenyl)acrylate

To a stirred solution of the bromobenzaldehyde (1.0 g, 5.4 mmol) inCH₂Cl₂ (20 mL) was added benzyl-2-(triphenylphosphoranylidene)acetateslowly and stirred for 10 minutes at rt. Then refluxed for 2 hours at50° C. and allowed to cool to r.t. The solution was concentrated underreduced pressure and purified on Biotage to yield a white solid, 1.32 g(77%), mp=97-99° C.; ¹H NMR (400 MHz, CDCl₃) δ 7.65 (d, J=16.0 Hz, 1H),7.51 (d, J=8.5 Hz, 2H), 7.44-7.32 (m, 7H), 6.47 (d, J=16.0 Hz, 1H), 5.25(s, 2H).

(b) [3-(adamantan-1-yl)-4-methoxyphenyl]boronic acid

To a solution of 1-(5-iodo-2-methoxyphenyl)adamantane or1-(5-bromo-2-methoxyphenyl)adamantane (2.0 g, 6.22 mmol) in dried THF(15 mL) at −78° C. was slowly added nBuLi of 2.5 M solution in hexane(3.0 mL) over 10 minutes. The solution was stirred for 1 hr andB(Oi-Pr)₃ (5.75 mL, 25 mmol) was added by a syringe at −78° C. Thesolution was stirred for 1 hr at −78° C. and then allowed to warm to rtovernight. The reaction was cooled to 0° C. followed by the sequentialaddition of water (1.5 mL) and 2 N HCl (1.5 mL). After 5 minutes, anadditional 27 mL (2N HCl) was added and stirred for 10 minutes. Themixture was extracted with 3×20 mL EtOAc and the combined organic layerswere concentrated to a thick oil. Crystallization with heptanes yieldedthe title compound as a yellow powder, 1.533 g (86%); M. p. 261-263° C.;R_(f)=0.55 (60% EtOAc: heptanes). ¹H NMR (500 MHz, cdcl₃) δ 8.15 (d,J=1.5 Hz, 1H), 8.05 (dd, J=8.1, 1.5 Hz, 1H), 7.00 (d, J=8.2 Hz, 1H),3.91 (s, 3H), 2.26-2.06 (m, 9H), 1.82 (s, 6H).

(c) benzyl(2E)-3-{4-[3-(adamantan-1-yl)-4-methoxyphenyl]phenyl}prop-2-enoate

In a 50 mL three-necked flask, equipped with a stirrer, a refluxcondenser and a gas inlet adapter was introduced 6.41 mg (0.5 mol %) oftris(dibenzylydeneacetone)dipalladium(0) Pd₂(dba)₃ and dissolved in 5 mLof tetrahydrofuran. Then 5.75 mg (1 mol %) of Sphos was added and thesolution stirred for 30 min under a slight stream of argon. To thereaction mixture 400 mg (1.4 mmol)3-(1-adamantyl)-4-methoxyphenylboronic acid and 444 mg (1.4 mmol) of(E)-Benzyl 3-(4-bromophenyl)acrylate were added and stirred until allcomponents were dissolved. A solution of 2 mL of 0.28 M of sodiumcarbonate was then added. The mixture was vigorously stirred for 4 hwith boiling at 80° C. under a slight stream of argon. The two layerswere separated and organic layer dried under MgSO₄, filtered andconcentrated under reduced pressure. Then it was purified on a HP-Sil 25g Biotage SNAP cartridge and eluted with EtOAc:heptane using a gradient(0-10%) at a flow rate of 20 mL/min to provide a white solid (498 mg,74%). mp=152-154° C.; ¹H NMR (400 MHz, CDCl₃) δ 7.76 (d, J=16.0 Hz, 1H),7.62-7.53 (m, 4H), 7.48 (d, J=2.2 Hz, 1H), 7.46-7.31 (m, 6H), 6.95 (d,J=8.5 Hz, 1H), 6.50 (d, J=16.0 Hz, 1H), 5.26 (s, 2H), 3.88 (s, 3H), 2.14(s, 6H), 2.08 (s, 3H), 1.78 (s, 6H).

Example 332(E)-3-{4-[3-(adamantan-1-yl)-4-methoxyphenyl]phenyl}prop-2-enoic acid

A suspension of the ester benzyl(2E)-3-{4-[3-(adamantan-1-yl)-4-methoxyphenyl]phenyl}prop-2-enoate (100mg, 0.21 mmol) in 1.0 mL of MeOH:H₂O (9:1) was treated with 25 mg (0.45mmol) of KOH and 0.1 mL THF. The reaction mixture was stirred for 5-6 hat 70-75° C., cooled to room temperature and quenched with water (5.0mL).The mixture was extracted with Et₂O (10 mL) and the aqueous layerwas acidified to pH 2 with 1N HCl and extracted with ethyl acetate (3×15mL). The combined organic phases were dried and evaporated. The residuewas crystallized from ethyl acetate-hexane to give 80 mg (99%) of theacid as white crystals. mp=327-328° C.; ¹H NMR (400 MHz, DMSO) δ 12.38(s, 1H), 7.73 (d, J=8.3 Hz, 2H), 7.65 (d, J=8.4 Hz, 2H), 7.61 (d, J=16.2Hz, 1H), 7.53 (dd, J=8.5, 2.1 Hz, 1H), 7.43 (d, J=2.2 Hz, 1H), 7.07 (d,J=8.6 Hz, 1H), 6.54 (d, J=16.0 Hz, 1H), 3.84 (s, 3H), 2.10 (s, 6H), 2.05(s, 3H), 1.74 (s, 6H) HRMS (TOF MS ES+) for C₂₆H₂₉O₃ ^(|) (MH+) calcd.389.2134, found 389.2117.

Example 34(2E)-3-{4-[3-(adamantan-1-yl)-4-hydroxyphenyl]phenyl}prop-2-enoic acid

Title compound was prepared according to example 31 starting from 70 mgof 2(E)-3-{4-[3-(adamantan-1-yl)-4-methoxyphenyl]phenyl}prop-2-enoicacid. The residue was purified on a HP-Sil 25 g Biotage SNAP cartridgeand eluted with EtOAc:heptane using a gradient (0-25%) at a flow rate of20 mL/min to provide a yellow solid (41 mg, 61%). mp=273-275° C.; ¹H NMR(400 MHz, DMSO) δ 9.62 (s, 1H), 7.68 (d, J=8.1 Hz, 2H), 7.60 (d, J=8.2Hz, 2H), 7.56 (d, J=16.0 Hz, 1H), 7.36 (d, J=7.9 Hz, 2H), 6.87 (d, J=7.9Hz, 1H), 6.53 (d, J=15.9 Hz, 1H), 2.13 (s, 6H), 2.05 (s, 3H), 1.74 (s,6H). HRMS (TOF MS ES+) for C₂₅H₂₇O₃ ⁺ (MH+) calcd. 375.1960, found375.1921.

Example 35 Benzyl(2E)-3-(4-{[3-(adamantan-1-yl)-4-methoxyphenyl]amino}phenyl)-prop-2-enoate(a) tert-butyl N-[4-(hydroxymethyl)phenyl]carbamate

A 100-mL, three-necked, round-bottomed flask, was equipped with amagnetic stirring bar, a reflux condenser, and a pressure-equalizingdropping funnel that was connected to a nitrogen flow line and chargedwith a solution of 97% di-tert-butyl dicarbonate (4.04 g, 18.5 mmol) intetrahydrofuran (30 mL). Amino benzyl alcohol (2.5 g, 20.3 mmol) wasplaced in the flask and suspended in tetrahydrofuran (65 mL) and 99%triethylamine (3.1 mL, 22 mmol). The resulting white suspension wascooled with an ice-water bath and the solution of di-tert-butyldicarbonate was added dropwise over a period of 30 minutes. After 10 minof additional stirring, the ice-water bath was removed and thesuspension was stirred overnight at room temperature, then warmed at 50°C. for a further 3 hours. The solvent was removed under reduced pressureand the residue partitioned between EtOAc (50 mL) and saturated aqueousbicarbonate solution (50 mL). The aqueous phase was extracted with three50-mL portions of EtOAc. The combined organic phases were dried withanhydrous MgSO₄ and concentrated under reduced pressure to give 3.72 g(83% yield) of the product as a brown oil that was used without furtherpurification. ¹H NMR (as rotamers) (400 MHz, CDCl₃) δ 9.26 (s, 1H), 8.64(s, 1H), 7.39 (4H), 7.20 (4H), 5.75 (s, 1H), 5.05 (2H), 4.49-4.35 (m,4H), 1.47 (s, 9H), 1.40 (s, 1H).

(b) tert-butyl N-(4-formylphenyl)carbamate

To a stirring solution of suspended pyridinium chlorochromate (3.84 g,17.81 mmol) in 100 ml of anhydrous CH₂Cl₂ was added tort-butylN-[4-(hydroxymethyl)phenyl]carbamate (2.65 g, 11.87 mmol) in 10 mL CHCl₂in one protion. After 1.5 hrs, TLC showed full consumption of thestarting material. Then filtered with a pad of celite and the resultingdark brown solution was rotary evaporated under reduced pressure. Theresidue was purified on a Biotage SNAP cartridge (100 g) using anEtOAc:cyclohexane gradient (0-20%) to yield a yellowish-white solid.Recrystallized from EtOAc/cyclohexane, 2.26 g (86%). M. p. 140-142° C.;¹H NMR (400 MHz, CDCl₃) δ 9.89 (s, 1H), 7.82 (d, J=8.6 Hz, 2H), 7.56 (d,J=8.6 Hz, 2H), 6.99 (s, 1H), 1.53 (s, 9H).

(c) benzyl (2E)-3-(4-{[(tert-butoxy)carbonyl]amino}phenyl)prop-2-enoate

To a stirred solution of aldehyde tert-butyl N-(4-formylphenyl)carbamate(1.16 g, 5.24 mmol) in CH₂Cl₂ (20 mL) was addedbenzyl-2-(triphenylphosphoranylidene)acetate slowly and stirred for 10minutes at r.t. Then refluxed for 2 hours at 50° C. and allowed to coolto rt. The solution was concentrated under reduced pressure and purifiedon Biotage to yield a white solid, 1.80 g (99%). M. p. 93-95° C. ¹H NMR(400 MHz, CDCl) δ 7.67 (d, J=16.0 Hz, 1H), 7.49-7.30 (9H), 6.65 (s, 1H),6.39 (d, J=16.0 Hz, 1H), 5.24 (s, 2H), 1.52 (s, 9H).

(d) benzyl (2E)-3-(4-aminophenyl)prop-2-enoate

To a stirring solution of benzyl(2E)-3-(4-{[(tert-butoxy)carbonyl]amino}phenyl)prop-2-enoate in CH₂Cl₂at 0° C. were added TFA and allowed to warm to r.t. over 2 hours. TLCshowed the reaction was complete. It was then quenched by addition of 30mL saturated NaHCO₃ solution and extracted 3×30 mL CH₂Cl₂. The combinedorganic phases was dried over MgSO₄ and concentrated under reducedpressure. The residue was purified on Biotage on a 50 g Biotage SNAPcartridge using 30% EtOAc:cyclohexane gradient to yield a yellow solid,1.043 g (85%). M. p. 112-114° C. ¹H NMR (400 MHz, CDCl₃) δ 7.64 (d,J=15.9 Hz, 1H), 7.43-7.29 (7H), 6.63 (d, J=8.5 Hz, 2H), 6.28 (d, J=15.9Hz, 1H), 5.23 (s, 2H), 3.93 (s, 2H).

(e) benzyl(2E)-3-(4-{[3-(adamantan-1-yl)-4-methoxyphenyl]amino}phenyl)prop-2-enoate

To a 20 mL scintilation vial equipped with a magnetic stir bar was addedthe 3-(1-adamantyl)-4-methoxyphenylboronic acid (600 mg, 2.1 mmol),benzyl (2E)-3-(4-aminophenyl)prop-2-enoate (531 mg, 2.1 mmol), anhydrouscupric acetate (384 mg, 2.1 mmol), 750 mg of activated 4 Å molecularsieves, pyridine (3.3 mL of 0.67M in CH₂Cl₂), and 15 mL CH₂Cl₂. Thereaction was stirred at room temperature in the loosely capped vial for2 days. The reaction was complete as shown by TLC analysis of analiquot. The reaction was filtered through Celite, washed with methanoland purified on a Biotage SNAP cartridge and eluted withEtOAc:cyclohexane using a gradient (0-15%) to provide a brown solid (661mg, 64%). M. p. 133-135° C.; Rf=0.38 (15% EtOAc:cyclohexane). 1H NMR(400 MHz, CDCl3) δ 7.65 (d, J=15.9 Hz, 1H), 7.46-7.29 (7H), 7.00 (dd,J=12.8, 2.5 Hz, 2H), 6.85-6.78 (m, 3H), 6.29 (d, J=15.9 Hz, 1H), 5.77(s, 1H), 5.23 (s, 2H), 3.83 (s, 3H), 2.06 (s, 9H), 1.76 (s, 6H). 13C NMR(101 MHz, CDCl3) δ 167.51, 155.54, 147.90, 145.33, 139.84, 136.40,133.42, 129.92, 128.52, 128.17, 128.08, 126.75, 126.42, 124.82, 121.72,120.45, 120.40, 114.27, 113.09, 112.43, 111.67, 66.00, 55.33, 40.52,37.13, 37.06, 37.03, 29.10, 29.02. HRMS (TOF MS ES+) for C33H36NO3+(MH+) calcd. 494.2695, found 494.2682.

Example 36(2E)-3-(4-{[3-(adamantan-1-yl)-4-methoxyphenyl]amino}phenyl)prop-2-enoicacid

(2E)-3-(4-{[3-(adamantan-1-yl)-4-methoxyphenyl]amino}phenyl)prop-2-enoicacid was prepared according to example 33 staring from 130 mg of benzyl(2E)-3-(4-{[3-(adamantan-1-yl)-4-methoxyphenyl]amino}phenyl)prop-2-enoate.The residue was purified on Biotage to give 69 mg (66%) of the acid.mp=197-200° C. ¹H NMR (400 MHz, DMSO) δ 12.03 (s, 1H), 8.32 (s, 1H),7.47 (d, J=8.3 Hz, 2H), 7.45 (d, J=15.9 Hz, 1H), 6.99 (dd, J=8.6, 2.4Hz, 1H), 6.94 (dd, J=9.3, 5.6 Hz, 2H), 6.88 (d, J=8.6 Hz, 2H), 6.21(d,J=15.8 Hz, 1H), 3.77 (s, 3H), 2.02 (s, 9H), 1.72 (s, 6H). HRMS (TOFMS ES+) for C₂₅H₃₀NO₃ ⁺ (MH+) calcd. 404.2226, found 404.2191.

Example 37(2E)-3-(4-{[3-(adamantan-1-yl)-4-hydroxyphenyl]amino}phenyl)prop-2-enoicacid

(2E)-3-(4-{[3-(adamantan-1-yl)-4-hydroxyphenyl]amino}phenyl)prop-2-enoicacid was prepared according to example 31 starting from 32 mg of(2E)-3-(4-{[3-(adamantan-1-yl)-4-methoxyphenyl]amino}phenyl)prop-2-enoicacid. The residue was purified on a HP-Sil 25 g Biotage SNAP cartridgeand eluted with EtOAc:cyclohexane using a gradient (0-25%) at a flowrate of 20 mL/min to provide a yellow solid (25 mg, 80%). mp=decomposesat 152° C. ¹H NMR (400 MHz, DMSO) δ 12.01 (s, 1H), 9.05 (s, 1H), 8.17(s, 1H), 7.50-7.39 (m, 3H), 6.86 (dd, J=9.8, 2.2 Hz, 2H), 6.82 (d, J=8.7Hz, 3H), 6.73 (d, J=8.3 Hz, 1H), 6.19 (d, J=15.9 Hz, 1H), 2.06 (s, 6H),2.02 (s, 3H), 1.72 (s, 6H). HRMS (TOF MS ES+) for C₂₃H₂₃NO₃ ⁺ (MH+)calcd. 390.2069, found 390.2045.

Example 383-(4-{[3-(adamantan-1-yl)-4-hydroxyphenyl]amino}phenyl)propanoic acid

Benzyl(2E)-3-(4-{[3-(adamantan-1-yl)-4-methoxyphenyl]amino}phenyl)prop-2-enoate(660 mg, 1.33 mmol) was placed in a hydrogenation apparatus equippedwith a magnetic stir bar and 50 mL ethanol/EtOAc added. Pd/C (300 mg) ina small amount of MeOH (3 mL) was added and stirring commenced. Hydrogengas was introduced at a pressure of 20 psi and reacted at rt for 5 hrs.TLC showed full conversion. The black solution was filtered using acelite pad and concentrated under reduced pressure. Further purificationon Biotage yielded a brown solid, 200 mg (30%). mp=164-166° C. ¹H NMR(400 MHz, CDCl₃) δ 8.39 (s, 1H), 7.05 (d, J=8.1 Hz, 2H), 6.95 (m, 2H),6.85 (d, J=7.4 Hz, 2H), 6.80 (d, J=8.5 Hz, 1H), 3.81 (s, 3H), 2.87 (d,7.0 Hz, 2H), 2.65 (t, J=7.7 Hz, 2H), 2.07 (s, 9H), 1.76 (s, 6H). HRMS(TOF MS ES+) for C₂₆H₃₂NO₃ ⁺ (MH+) calcd. 406.2382, found 406.2410.

Example 393-(4-{[3-(adamantan-1-yl)-4-hydroxyphenyl]amino}phenyl)propanoic acid

3-(4-{[3-(adamantan-1-yl)-4-hydroxyphenyl]amino}phenyl)propanoic acidwas prepared according to example example 31 starting from 80 mg of3-(4-{[3-(adamantan-1-yl)-4-methoxyphenyl]amino}phenyl)propanoic acid.The residue was purified on Biotage to provide a dark green solid (58mg, 75%). mp 94-96° C. ¹H NMR (400 MHz, DMSO) δ 12.05 (s, 1H), 8.83 (s,1H), 6.98 (d, J=8.4 Hz, 2H), 6.81 (d, J=2.5 Hz, 1H), 6.77 (d, J=8.4 Hz,2H), 6.74 (dd, J=8.3, 2.5 Hz, 1H), 6.65 (d, J=8.4 Hz, 1H), 2.68 (t,J=7.6 Hz, 2H), 2.45 (t, J=7.6 Hz, 2H), 2.05 (s, 6H), 2.01 (s, 3H), 1.71(s, 6H). HRMS (TOF MS ES+) for C₂₅H₃₀NO₃ ⁺ (MH+) calcd, 392.2226, found392.2246.

Example 40 Benzyl(2E)-3-{4-[(3-tert-butyl-4-methoxyphenyl)amino]phenyl}prop-2-enoate4-bromo-2-tert-butylphenol

4-bromo-2-tert-butylphenol was prepared according to a proceduredescribed by Berthelot and al. (Can. J. Chem, 1989, 67, 2061-2066). To asolution of 2-tert-butylphenol (154 mL, 1 mmol, 1 eq.) in chloroform (5mL) was added a solution of TBABr₃ (482 mg, 1 mmol, 1 eq.) in chloroform(5 mL). The orange solution became colorless within 5 minutes. Asolution of 5% sodium thiosulfate was added (15 mL). The organic layeris extracted with chloroform (2×20 mL), washed with water until pH=7,and evaporated. The crude oil is then diluted in diethyl ether (50 mL)and washed with water again (2×20 mL). The organic layer is then driedover Ca₂SO₄ and concentrated to dryness to afford a yellow solid (201mg, 88%). mp=101° C. No further purification is needed. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.38 (s, 9H), 4.96 (s, 1H), 6.58 (d, J=8.37 Hz, 1H),7.15 (dd, J=8.37, 2.41 Hz, 1H), 7.34 (d, J=2.41 Hz, 1H).

(a) 4-bromo-2-tert-butyl-1-methoxybenzene

4-bromo-2-test-butyl-1-methoxybenzene was prepared according example55(a), starting from 610 mg of 4-bromo-2-tert-butylphenol. A lightorange oil is obtained (500 mg, 78%).¹H NMR (400 MHz, CHLOROFORM-d) δppm 1.34 (m, 9H,), 3.81 (m, 3H), 6.73 (d, J=8.66 Hz, 1H), 7.23-7.29 (m,1H), 7.35 (d, J=2.38 Hz, 1H).

(b) 3-tert-butyl-4-methoxyphenyl)boronic acid

3-tert-butyl-4-methoxyphenyl)boronic acid was prepared according toexample 32(b), starting from 500 mg of4-bromo-2-tert-butyl-1-methoxybenzene. The crude sticky oil obtained,was used in in the following step without any purification.

(c) benzyl(2E)-3-{4-[(3-tert-butyl-4-methoxyphenyl)amino]phenyl}prop-2-enoate

Benzyl(2E)-3-{4-[(3-tert-butyl-4-methoxyphenyl)amino]phenyl}prop-2-enoate wasobtained according to example 35(e), starting from 100 mg of3-tert-butyl-4-methoxyphenyl)boronic acid. a\After purification bycolumn chromatography using the following gradient system,(cyclohexane/ethyl acetate): (97/3) to (60/40), to yield the titlecompound as colorless oil (60 mg, 60%). ¹H NMR (400 MHz, CHLOROFORM-d) δppm 1.34 (m, 9H), 3.84 (s, 3H), 5.23 (s, 2H), 5.77 (s, 1H), 6.29 (d,J=15.87 Hz, 1H), 6.83 (t, J=8.22 Hz, 3H), 6.95-7.11 (m, 2H), 7.29-7.47(m, 7H), 7.65 (d, J=15.87 Hz, 1H).

Example 41 3-{4-[(3-tert-butyl-4-methoxyphenyl)amino]phenyl}propanoicacid

3-{4-[(3-tert-butyl-4-methoxyphenyl)amino]phenyl}propanoic acid wasprepared according to example 38, starting from 2245 mg of benzyl(2E)-3-{4-[(3-tert-butyl-4-methoxyphenyl)amino]phenyl}prop-2-enoate. Ablack sticky oil was obtained (73 mg, 38%). ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.36 (s, 9H), 2.65 (t, J=7.75 Hz, 2H), 2.88 (t,J=7.75 Hz, 2H), 3.82 (s, 3H), 5.30 (s, 1H), 6.76-6.90 (m, 3H), 6.96 (dd,J=8.53, 2.64 Hz, 1H), 6.99-7.12 (m, 3H). HRMS (TOF MS ES−) forC20H24NO3− (M−H)− calcd. 326.1756, found 326.1740.

Example 42 Methyl(2E)-3-{4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dioxolan-2-yl]phenyl}prop-2-enoate(a)(4-iodophenyl)(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methanone

Compound was prepared according to the procedure described by Boehm etal. (J. Med. Chem. 1994, 37, 2930-2941) starting from 4 g of4-iodobenzoic acid (16.1 mmol). After work-up, the crude product waspurified by column chromatography using the following gradient system,(cyclohexane/dichloromethane): (80/20) to (0/100), to yield the titlecompound as a light orange solid, 2.8 g (50%). mp=7576° C. ¹H NMR (400MHz, CHLOROFORM-d) δ 1.31 (2s, 12H), 1.72 (s, 4H), 7.40 (d, J=8.16 Hz,1H), 7.45-7.60 (m, 3H), 7.75 (d, J=1.63 Hz, 1H), 7.84 (d, J=8.28 Hz,2H).

(b)2-(4-iodophenyl)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dioxolane

(4-iodophenyl)(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methanone(2 g, 4.78 mmol) was treated with ethylene glycol (20 mL) and acatalytic amount of pTsOH (200 mg) in toluene (120 mL) at 145° C.overnight using a Dean Stark trap. After cooling to r.t., the mixturewas washed with saturated aqueous NaHCO₃, brine, dried over Ca₂SO₄ andconcentrated under reduced pressure. The residue was purified by columnchromatography using the following gradient system,(cyclohexane/dichloromethane): (80/20) to (0/100), to yield the titlecompound as a white solid (1.1 g, 50%) and the starting material (1 g).The reaction was repeated by sequences with the unreacted ketone untilfully converted. mp=116-117° C. ¹H NMR (400 MHz, CHLOROFORM-d) δ 1.24(2s, 12H), 1.65 (s, 4H), 3.85-4.15 (m, 4H), 7.14 (dd, J=1.76, 8.16 Hz,1H), 7.22 (d, J=8.16 Hz, 1H), 7.28 (s, 1H), 7.38-7.46 (m, 1H), 7.65 (d,J=8.53 Hz, 3H).

(c) Methyl(2E)-3-{4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dioxolan-2-yl]phenyl}prop-2-enoate

To a stirred solution of2-(4-iodophenyl)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dioxolane(1.02 g, 2.2 mmol, 1 eq.) and Et₃N (920 μL, 6.6 mmol, 3 eq.) were addedmethyl acrylate (300 μL, 3.3 mmol, 1.5 eq.) and palladium (II) acetate(15 mg, 0.1 eq.). The resulting mixture was heated at 100° C. for 3hours. The reaction mixture was allowed to cool to r.t., concentratedunder reduced pressure and purified by column chromatography using thefollowing gradient system, (cyclohexane/dichloromethane): (80/20) to(0/100), to yield the title compound as a white solid, 0.75 g (80%).mp=168-170° C. 1H NMR (400 MHz, CHLOROFORM-d) δ 1.24 (2s, 12H), 1.65 (s,4H), 3.80 (s, 3H), 3.96-4.14 (m, 4H), 6.42 (d, J=15.94 Hz, 1H),7.13-7.20 (m, 1H), 7.23 (d, J=8.16 Hz, 1H), 7.40-7.60 (m, 5H), 7.67 (d,J=15.94 Hz, 1H).

Example 43 Methyl3-{4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dioxolan-2-yl]phenyl}propanoate

A solution of methyl(2E)-3-{4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dioxolan-2-yl]phenyl}prop-2-enoate(750 mg, 1.78 mmol) in 60 mL of (EtOH/EtOAc:(9/1) was placed in ahydrogenation apparatus equipped with a magnetic stir bar. Pd/C (410 mg)in a small amount of MeOH (2 mL) was added. Hydrogen gas was introducedat a pressure of 20 psi and reacted at r.t. overnight. The blacksolution was filtered using a celite pad and concentrated under reducedpressure. Further purification by chromatography yielded the titlecompound as a white solid, 520 mg (70%). mp 120-122° C. ¹H NMR (400 MHz,CHLOROFORM-d) δ 1.24 (2s, 12H), 1.65 (s, 4H), 2.61 (t, J=7.84 Hz, 2M,2.93 (t, J=7.84 Hz, 2H), 3.66 (s, 3H), 3.93-4.13 (m, 4H), 7.10-7.19 (m,3H), 7.19-7.24 (m, 3H), 7.38-7.49 (m, 3H).

Example 443-{4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dioxolan-2-yl]phenyl}propanoicacid

3-{4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dioxolan-2-yl]phenyl}propanoicacid was prepared according to example 3 starting from 250 mg of methyl3-{4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dioxolan-2-yl]phenyl}propanoate(example 43). The title compound was obtained as a white solid (220 mg,91%). mp=219°-220° C. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.23 (s, 6H),1.24 (s, 6H), 1.65 (s, 4H), 2.66 (t, J=7.78 Hz, 2H), 2.94 (t, J=7.84 Hz,2H), 3.97-4.09 (m, 4H), 7.17 (m, 3H), 7.19-7.24 (d, J=8.28 Hz 1H), 7.44(m, 3H). HRMS (ESI+) [M+H]⁺ for C₂₅H₃₃O₄ ⁺(MH⁺) 419.0836, calc.419.0866.

Example 45 Methyl3-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-carbonyl)phenyl]propanoate

A mixture of methyl3-{4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dioxolan-2-yl]phenyl}propanoate(265 mg, 0.63 mmol, 1 eq.), iodine (160 mg, 0.63 mmol, 1 eq.) and 4 Åmolecular sieves (250 mg) in acetone (6 mL) was stirred for 8 hoursunder reflux according to a modified method of Sun et al, (J. Org. Chem.2004, 69, 8932-8934.). After work-up and purification by columnchromatography using the following gradient system,(cyclohexane/dichloromethane):(80/20) to (20/80), the title compound wasobtained as a colorless oil (150 mg, 63%). ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.30 (s, 6H), 1.31 (s, 6H), 1.72 (s, 4H), 2.69 (t,J=7.72 Hz, 2H), 3.04 (t, J=7.78 Hz, 2H), 3.69 (s, 3H), 7.31 (d, J=7.91Hz, 2H), 7.39 (d, J=8.16 Hz, 1H), 7.53 (d, J=8.16 Hz, 1H), 7.71-7.80 (m,3H).

Example 463-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-carbonyl)phenyl]propanoicacid

3-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-carbonyl)phenyl]propanoicacid was prepared according to example 3 using 50 mg of correspondingester (example 45). A white solid is obtained (220 mg, 91%). mp153°-155° C. ¹H NMR (400 MHz, CHLOROFORM-d) δ 1.31 (2s, 12H), 1.72 (s,6H), 2.75 (t, J=7.72 Hz, 2H), 3.05 (t, J=7.72 Hz, 2H), 7.32 (d, J=8.16Hz, 2H), 7.39 (d, J=8.28 Hz, 1H), 7.53 (dd, J=1.82, 8.22 Hz, 1H),7.70-7.83 (m, 3H). HRMS (ESI+) [M+H]⁺ for C₂₃H₂₉O₃ ⁺(MH⁺) 419.0836,calc. 419.0866.

Example 47 Methyl(2E)-3-{4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]phenyl}prop-2-enoate

Methyl(2E)-3-{4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]phenyl}-prop-2-enoatewas prepared according to example 42(c) starting from 1.65 g of(4-iodophenyl)(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methanone.The crude was purified on Biotage to yield a yellow solid, 1.22 g (82%),mp=138-140° C. ¹H NMR (400 MHz, CDCl₃) δ 7.82 (d, J=8.3 Hz, 2H), 7.79(d, J=1.8 Hz, 1H), 7.75 (d, J=16.1 Hz, 1H), 7.63 (d, J=8.3 Hz, 2H), 7.54(dd, J=8.2, 1.9 Hz, 1H), 7.41 (d, J=8.2 Hz, 1H), 6.55 (d, 16.0 Hz, 1H),3.83 (s, 3H), 1.72 (s, 4H), 1.32 (s, 6H), 1.30 (s, 6H).

Example 48 Methyl(2E)-3-{4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dithiolan-2-yl]phenyl}prop-2-enoate

To a solution of methyl(2E)-3-{4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]phenyl}prop-2-enoate(0.35 g, 0.93 mmol) example 47, in CH₂Cl₂ (20 mL) at 0° C. under Ar wasadded a solution of ethanedithiol (117 mL, 1.40 mmol, 1.5 eq.) in CH₂Cl₂(0.5 mL) followed by BF₃.Et₂0 (177 μL, 1.40 mmol,). The resultingmixture was stirred at 0° C. for 1 h and then warmed to room temperatureovernight. The reaction was quenched by pouring the mixture intosaturated Na₂CO₃, and the mixture was extracted (CH₂Cl₂). The combinedorganic layers were dried (MgSO₄) and concentrated to afford a colorlessoil (380 mg (91%). ¹H NMR (400 MHz, CDCl₃) δ 7.67 (d, J=16.2 Hz, 1H),7.66 (d, J=8.4 Hz, 2H), 7.50 (d, J=2.0 Hz, 1H), 7.44 (d, J=8.4 Hz, 2H),7.22 (dd, J=8.4, 2.1 Hz, 1H), 7.18 (d, J=8.3 Hz, 1H), 6.42 (d, J=16.0Hz, 1H), 3.80 (s, 3H), 3.50-3.40 (m, 2H), 3.42-3.32 (m, 2H), 1.66 (s,4H), 1.25 (s, 6H), 1.21 (s, 6H).

Example 49(2E)-3-{4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dithiolan-2-yl]phenyl}prop-2-enoicacid

(2E)-3-{4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dithiolan-2-yl]phenyl}prop-2-enoicacid was prepared according to example 3 starting from 85 mg of methyl(2E)-3-{4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dithiolan-2-yl]phenyl}prop-2-enoate.Title compound was obtained as a white solid, 81 mg (97%). mp=234-236°C. ¹H NMR (400 MHz, CDCl₃) δ 7.77 (d, J=15.9 Hz, 1H), 7.68 (d, J=8.4 Hz,2H), 7.50 (d, J=2.0 Hz, 1H), 7.47 (d, J=8.4 Hz, 2H), 7.22 (dd, J=8.4,2.1 Hz, 1H), 7.18 (d, J=8.3 Hz, 1H), 6.43 (d, J=16.0 Hz, 1H), 3.46 (ddd,J=12.3, 9.4, 7.4 Hz, 2H), 3.42-3.34 (m, 2H), 1.66 (s, 4H), 1.25 (s, 6H),1.21 (s, 6H), HRMS (TOF MS ES+) for C₂₆H₃₄O₂S₂(MH⁺) calcd. 439.1765,found 439.1765.

Example 50(2E)-3-{4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]phenyl}prop-2-enoicacid

(2E)-3-{4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]phenyl}prop-2-enoicacid was prepared according to example 3, starting from 310 mg of methyl(2E)-3-{4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]phenyl}prop-2-enoate.The crude was purified on Biotage to provide a white solid (278 mg,93%). mp=220-221° C., ¹H NMR (400 MHz, CDCl₃) δ 7.85 (d, J=16.8 Hz, 1H),7.84 (d, J=8.0 Hz, 1H), 7.80 (d, J=1.8 Hz, 1H), 7.66 (d, J=8.2 Hz, 2H),7.54 (dd, J=8.2, 1.8 Hz, 1H), 7.41 (d, J=8.2 Hz, 1H), 6.57 (d, J=16.0Hz, 1H), 1.73 (s, 4H), 1.32 (s, 6H), 1.30 (s, 6H).

Example 51 Methyl3-{4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dithiolan-2-yl]phenyl}propanoate

Methyl3-{4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dithiolan-2-yl]phenyl}propanoatewas prepared according to example 48, starting from 30 mg of methyl3-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-carbonyl)phenyl]propanoateto provide a colorless oil (25 mg, 69%). ¹H NMR (400 MHz, CDCl₃) δ 7.54(d, J=8.4 Hz, 2H), 7.52 (d, J=2.1 Hz, 1H), 7.22 (dd, J=8.4, 2.2 Hz, 1H),7.16 (d, J=8.4 Hz, 1H), 7.11 (d, J=8.3 Hz, 2H), 3.67 (s, 3H), 3.48-3.29(m, 4H), 2.93 (t, J=7.9 Hz, 2H), 2.62 (t, J=7.9 Hz, 2H), 1.65 (s, 4H),1.24 (s, 6H), 1.21 (s, 6H).

Example 523-{4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2yl)-1,3-dithiolan-2-yl]phenyl}propanoicacid

3-{4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dithiolan-2-yl]phenyl}propanoicacid was prepared according to example 3, starting from 25 mg of Methyl3-{4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dithiolan-2-yl]phenyl}propanoate.The residue was purified on Biotage to give title compound as a yellowsolid (15 mg, 63%), mp=165-167° C. ¹H NMR (400 MHz, CDCl₃) δ 7.55 (d,J=8.3 Hz, 2H), 7.52 (d, J=2.1 Hz, 1H), 7.22 (dd, J=8.4, 2.2 Hz, 1H),7.16 (d, J=8.4 Hz, 1H), 7.12 (d, J=7.4 Hz, 2H), 3.49-3.32 (m, 4H), 2.94(t, J=7.8 Hz, 2H), 2.67 (t, J=7.8 Hz, 2H), 1.65 (s, 4H), 1.25 (d, J=1.7Hz, 6H), 1.21 (s, 6H). HRMS (TOF MS ES+) for C₂₆H₃₃O₂S₂ ⁻ (MH+) calcd.441.1922, found 441.1918.

Example 53 Methyl3-{4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methyl]phenyl}propanoate

Methyl3-{4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methyl]phenyl}-propanoatewas prepared according to example 38, starting from 515 mg of methyl(2E)-3-{4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]phenyl}prop-2-enoate.The crude was purified on a 50 g Biotage cartridge using anEtOAc:cyclohexane gradient (0-10%) to provide a colorless oil (479 mg,93%). ¹H NMR (400 MHz, CDCl₃) δ 7.19 (d, J=8.1 Hz, 1H), 7.15-7.08(Aroamtic, 5H), 6.90 (dd, J=8.1, 1.9 Hz, 1H), 3.89 (s, 2H), 3.65 (s,3H), 2.91 (t, J=7.9 Hz, 2H), 2.61 (t, J=7.9 Hz, 2H), 1.66 (s, 4H), 1.25(s, 12H).

Example 543-{4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methyl]phenyl}propanoicacid

3-{4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methyl]phenyl}propanoicacid was prepared according to example 3, starting from 422 mg of methyl3-{4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methyl]phenyl}propanoate.The crude was purified on a Biotage SNAP cartridge and eluted with 5%MeOH:CH₂Cl₂ to provide a white solid (301 mg, 77%). ¹H NMR (400 MHz,CDCl₃) δ 7.20 (d, J=8.1 Hz, 1H), 7.12 (5H), 6.90 (dd, J=8.1, 1.8 Hz,1H), 3.89 (s, 2H), 2.92 (t, J=7.8 Hz, 2H), 2.66 (t, J=7.8 Hz, 2H), 1.66(s, 4H), 1.25 (s, 12H). mp=142-143° C. HRMS (TOF MS ES+) for C₂₄H₃₁O₂(MH+) calcd. 351.2324, found 351.2321.

Example 55 Benzyl(2E)-3-{4[(3-tert-butyl-4-methoxyphenyl)carbonyl]phenyl}prop-2-enoate(a) 1-tert-butyl-2-methoxybenzene

To a suspension of sodium hydroxide (60% in oil, 0.46 g, 1.1 eq.) in DMF(5 mL), was slowly added a solution of 2-tertbutylphenol (1.53 g, 10mmol, 1 eq.) in DMF (5 mL). The mixture was stirred 1 hour until thesolution became clear. Iodomethane (0.68 mL, 1.1 eq.) was the added, andthe solution stirred for a further 2 hours. The mixture was poured intowater, and extracted with Et₂O. The organic layers were combined, driedwith brine and Ca₂SO₄, and concentrated to afford the title compound asa colorless oil (1.40 g, 80%). No further purification was needed. ¹HNMR (400 MHz, CHLOROFORM-d) δ ppm 1.37 (s, 9H), 3.82 (s, 3H), 6.83-6.93(m, 2H), 7.13-7.23 (m, 1H), 7.28 (dd, J=7.65, 1.38 Hz, 1H).

(b) (3-tert-butyl-4-methoxyphenyl)(4-iodophenyl)methanone

(3-tert-butyl-4-methoxyphenyl)(4-iodophenyl)methanone was preparedaccording to example 42(a), starting from 1.40 g of1-tert-butyl-2-methoxybenzene. Purification of crude by silica gelchromatography using the following gradient system,(cyclohexane/dichloromethane): (80/20) to (0/100), afforded(3-tert-butyl-4-methoxyphenyl)(4-iodophenyl)methanone as a colorless oil(1.1 g, 32%), alongside 4-tert-butyl-2-[(4-iodophenyl)carbonyl]phenol asa yellow solid (1.05 g, 31%). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.39(s, 9H) 3.92 (s, 3H) 6.90 (d, J=8.53 Hz, 1H) 7.48 (d, J=8.16 Hz, 2H)7.63 (dd, J=8.41, 2.01 Hz, 1H) 7.78-7.87 (m, 3H).

(c) 4-tert-butyl-2-[(4-iodophenyl)carbonyl]phenol

4-tert-butyl-2-[(4-iodophenyl)carbonyl]phenol was obtained in example55(b). Yellow solid (1.05 g, 30%). mp=101-103° C. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.25 (s, 9H), 7.02 (d, J=8.78 Hz, 1H), 7.42 (m,J=8.41 Hz, 2H), 7.52 (d, J=2.28 Hz, 1H), 7.58 (dd, J=8.78, 2.28 Hz, 1H),7.88 (m, J=8.41 Hz, 2H), 11.70 (s, 1H).

(d) Benzyl(2E)-3-{4-[(3-tert-butyl-4-methoxyphenyl)carbonyl]phenyl}prop-2-enoate

Ethyl(2E)-3-{4-[(3-tert-butyl-4-methoxyphenyl)carbonyl]phenyl}prop-2-enoatewas prepared according example 42(e), starting from 355 mg of(3-tert-butyl-4-methoxyphenyl)(4-iodophenyl)methanone. Purification ofthe crude by silica gel chromatography using the following gradientsystem, (cyclohexane/dichloromethane): (20/80) to (0/100), affordedtitle compound as a colorless oil (330 mg, 85%). ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.39 (s, 9H), 3.93 (s, 3H), 5.27 (s, 2H), 6.59 (d,J=16.06 Hz, 1H), 6.91 (d, J=8.53 Hz, 1H), 7.31-7.47 (m, 5H), 7.56-7.69(m, 3H), 7.72-7.83 (m, 3H), 7.86 (d, J=2.01 Hz, 1H).

Example 56 3-{4-[(3-tert-butyl-4-methoxyphenyl)methyl]phenyl}propanoicacid

3-{4-[(3-tert-butyl-4-methoxyphenyl)methyl]phenyl}propanoic acid wasprepared according to example 38 starting from 330 mg of ethyl(2E)-3-{4-[(3-tert-butyl-4-methoxyphenyl)carbonyl]phenyl}prop-2-enoate.Purification of the crude by silica gel chromatography using thefollowing gradient system, (dichloromethane/methanol): (98/2) to(80/20), afforded the title compound as a light yellow solid (152 mg,50%). mp 47-48° C. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.35 (s, 9H),2.66 (t, J=7.75 Hz, 2H), 2.92 (t, J=7.75 Hz, 2H), 3.80 (s, 3H), 3.88 (s,2H), 6.78 (d, J=8.28 Hz, 1H), 6.94 (d, J=8.16 Hz, 1H), 7.12 (s, 5H).HRMS (TOF MS ES−) for C21H25O3− (M−H)− calcd. 325.1804, found 325.1801.

Example 57 Methyl(2E)-3-{4-[(3-tert-butyl-4-methoxyphenyl)carbonyl]phenyl}prop-2-enoate

Methyl(2E)-3-{4-[(3-tert-butyl-4-methoxyphenyl)carbonyl]phenyl}prop-2-enoatewas prepared according example 42(e), starting from 600 mg of(3-tert-butyl-4-methoxyphenyl)(4-iodophenyl) methanone. Purification ofthe crude by silica gel chromatography using the following gradientsystem, (cyclohexane/dichloromethane): (20/80) to (0/100), affordedtitle compound as a white solid (410 mg, 76%). mp=128-129° C. ¹H NMR(400 MHz, CHLOROFORM-d) δ ppm 1.39 (s, 9H), 3.83 (s, 3H), 3.93 (s, 3H),6.54 (d, J=16.06 Hz, 1H), 6.91 (d, J=8.53 Hz, 1H), 7.57-7.69 (m, 3H),7.71-7.81 (m, 3H), 7.87 (d, J=2.01 Hz, 1H).

Example 58(2E)-3-{4-[(3-tert-butyl-4-methoxyphenyl)carbonyl]phenyl}prop-2-enoicacid

(2E)-3-{4-[(3-tert-butyl-4-methoxyphenyl)carbonyl]phenyl}prop-2-enoicacid was prepared according to example 3 using 30 mg of methyl(2E)-3-{4-[(3-tert-butyl-4-methoxyphenyl)carbonyl]phenyl}prop-2-enoate.A white solid is obtained (28 mg, 90%). mp=237-238° C. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.38 (s, 9H), 3.94 (s, 3H), 6.69 (d, J=15.94 Hz, 1H),7.16 (d, J=8.66 Hz, 1H), 7.58-7.82 (m, 5H), 7.88 (d, J=8.16 Hz, 2H),12.59 (s, 1H). HRMS (TOF MS ES−) for C21H21O4− (M−H)− calcd. 337.1440,found 337.1436.

Example 59 Methyl(2E)-3-{4-[2(3-tert-butyl-4-methoxyphenyl)-1,3-dioxolan-2-yl]phenyl}prop-2-enoate

Methyl(2E)-3-{4-[2-(3-tert-butyl-4-methoxyphenyl)-1,3-dioxolan-2-yl]phenyl}prop-2-enoatewas prepared according example 42(b), starting from 660 mg methyl(2E)-3-{4-[(3-tert-butyl-4-methoxyphenyl)carbonyl]phenyl}prop-2-enoate.Purification of the crude by silica, gel chromatography using thefollowing gradient system, (cyclohexane/ethyl acetate): (93/7) to(65/35), afforded the title compound as a white solid (490 mg, 65%).mp=132-133° C. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.34 (s, 9H),3.74-3.84 (m, 6H), 3.95-4.14 (m, 4H), 6.42 (d, J=16.00 Hz, 1H), 6.79 (d,J=8.53 Hz, 1H), 7.20-7.25 (m, 1H), 7.39-7.44 (m, 1H), 7.45-7.58 (m, 4H),7.68 (d, J=16.00 Hz, 1H).

Example 60 Methyl3-{4-[2-(3-tert-butyl-4-methoxyphenyl)-1,3-dioxolan-2-yl]phenyl}propanoate

Methyl3-{4-[2-(3-tert-butyl-4-methoxyphenyl)-1,3-dioxolan-2-yl]phenyl}propanoatewas prepared according to example 38, starting from 250 mg of methyl(2E)-3-{4-[2-(3-tert-butyl-4-methoxyphenyl)-1,3-dioxolan-2-yl]phenyl}prop-2-enoate.Purification of the crude by silica gel chromatography using thefollowing gradient system, (cyclohexane/ethyl acetate): (93/7) to(60/40), afforded the title compound as a colorless oil (210 mg, 81%).¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.34 (s, 9H), 2.61 (t, J=7.91 Hz,2H), 2.87 (t, J=7.91 Hz, 2H), 3.66 (s, 3H), 3.80 (s, 3H), 6.78 (d,J=8.44 Hz, 1H), 7.15 (d, J=8.03 Hz, 2H), 7.23 (dd, J=8.44, 2.20 Hz, 1H),7.36-7.47 (m, 3H).

Example 613-{4-[2-(3-tert-butyl-4-methoxyphenyl)-1,3-dioxolan-2-yl]phenyl}propanoicacid

3-{4-[2-(3-tert-butyl-4-methoxyphenyl)-1,3-dioxolan-2-yl]phenyl}propanoicacid was prepared according to example 3 starting from 158 mg of methyl3-{4-[2-(3-tert-butyl-4-methoxyphenyl)-1,3-dioxolan-2-yl]phenyl}propanoate.A white solid is obtained (148 mg, 97%). mp=121° C. NMR (400 MHz,CHLOROFORM-d) δ ppm 1.34 (s, 9H), 2.66 (t, J=7.78 Hz, 2H), 2.91 (t,J=7.78 Hz, 2H), 3.80 (s, 3H), 3.94-4.13 (m, 4H), 6.79 (d, J=8.44 Hz,1H), 7.17 (d, J=7.91 Hz, 2H), 7.23 (dd, J=8.44, 1.69 Hz, 1H), 7.38-7.47(m, 3H). HRMS (TOF MS ES−) for C23H27O5− (M−H)− calcd. 383.1858, found383.1864.

Example 62 Benzyl 3-[4-(5-tert-butyl-2-methoxybenzoyl)phenyl]propanoate(a) (5-tert-butyl-2-methoxyphenyl)(4-iodophenyl)methanone

(5-tert-butyl-2-methoxyphenyl)(4-iodophenyl)methanone was preparedaccording to example 55(a) starting with 510 mg of4-tert-butyl-2-[(4-iodophenyl)carbonyl]phenol. Purification of the crudeby silica gel chromatography using the following gradient system,(cyclohexane/dichloromethane): (88/12) to (0/100), afforded the titlecompound as a colorless oil (515 mg, 97%). ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.31 (s, 9 H), 3.69 (s, 3H), 6.91 (d, J=8.78 Hz,1H), 7.37 (d, J=2.38 Hz, 1H), 7.46-7.55 (m, 3H), 7.79 (d, J=8.41 Hz,2H).

(b) Benzyl 3-[4-(5-tert-butyl-2-methoxybenzoyl)phenyl]propanoate

(3E)-4-{4-[(5-tert-butyl-2-methoxyphenyl)carbonyl]phenyl}but-3-en-2-onewas prepared according to example 42(e) starting from 530 mg of(5-tert-butyl-2-methoxyphenyl)(4-iodophenyl)methanone. Purification ofthe crude by silica gel chromatography using the following gradientsystem, (cyclohexane/ethyl acetate): (95/5) to (60/40), afforded thetitle compound as a colorless oil (771 mg, 71%). ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.31 (s, 9H), 3.68 (s, 3H), 6.57 (d, J=16.06 Hz,1H), 6.92 (d, J=8.75 Hz, 1H), 7.31-7.46 (m, 6H), 7.50 (dd, J=8.75, 2.57Hz, 1H), 7.57 (m, J=8.28 Hz, 2H), 7.75 (d, J=16.06 Hz, 1H), 7.82 (m,J=8.28 Hz, 2H).

Example 63 3-{4-[(5-tert-butyl-2-methoxyphenyl)methyl]phenyl}propanoicacid

3-{4-[(5-tert-butyl-2-methoxyphenyl)methyl]phenyl}propanoic acid wasprepared according to example 38 using 235 mg of(3E)-4-{4-[(5-tert-butyl-2-ethoxyphenyl)carbonyl]phenyl}but-3-en-2-one.A white solid is obtained (120 mg, 67%). mp=97-98° C. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.20-1.36 (m, 9H), 2.65 (t, J=7.78 Hz, 2H), 2.91 (t,J=7.78 Hz, 2H), 3.77 (s, 3H), 3.93 (s, 2H), 6.79 (d, J=8.50 Hz, 1H),7.05-7.18 (m, 5H), 7.20 (dd, J=8.50, 2.45 Hz, 1H). HRMS (TOF MS ES−) forC21H25O3− (M−H)− calcd. 325.1804, found 325.1794.

Example 64 Benzyl(2E)-3-[4-(5-tert-butyl-2-hydroxybenzoyl)phenyl]prop-2-enoate

(3E)-4-{4-[(5-tert-butyl-2-hydroxyphenyl)carbonyl]phenyl}but-3-en-2-onewas prepared according to example 42(c) starting from 515 mg of4-tert-butyl-2-[(4-iodophenyl)carbonyl]phenol. Purification of the crudeby silica gel chromatography using the following gradient system,(cyclohexane/dichloromethane): (80/20) to (0/100), afforded the titlecompound as a yellow solid (445 mg, 88%). mp=111° C. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.25 (s, 9H), 5.28 (s, 2H), 6.61 (d, J=16.06 Hz,1H), 7.03 (d, J=8.72 Hz, 1H), 7.32-7.46 (m, 5H), 7.54 (d, J=2.26 Hz,1H), 7.58 (dd, J=8.72, 2.38 Hz, 1H), 7.63-7.75 (m, 5H), 7.79 (d, J=16.06Hz, 1H), 11.75 (s, 1H).

Example 65 3-{4-[(5-tert-butyl-2-hydroxyphenyl)methyl]phenyl}propanoicacid

3-{4-[(5-tert-butyl-2-hydroxyphenyl)methyl]phenyl}propanoic acid wasprepared according to example 38 starting from 143 mg of benzyl(2E)-3-[4-(5-tert-butyl-2-hydroxybenzoyl)phenyl]prop-2-enoate.Purification of the crude by silica gel chromatography using thefollowing gradient system, (dichloromethane/methanol): (98/2) to(80/20), afforded the title compound as a white solid (77 mg, 72%).mp=98-99° C. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28 (s, 9H), 2.65 (t,J=7.78 Hz, 2H), 2.92 (t, J=7.78 Hz, 2H), 3.96 (s, 2H), 6.71 (d, J=9.03Hz, 1H), 7.04-7.22 (m, 6H).

Example 66 Benzyl(2E)-3-{4-[2-(5-tert-butyl-2-methoxyphenyl)-1,3-dioxolan-2-yl]phenyl}prop-2-enoate

(3E)-4-{4-[2-(5-tert-butyl-2-methoxyphenyl)-1,3-dioxolan-2-yl]phenyl}but-3-en-2-onewas prepared according to example 42(b), starting from 350 mg of (b)Benzyl 3-[4-(5-tert-butyl-2-methoxybenzoyl)phenyl]propanoate.Purification of the crude by silica gel chromatography using thefollowing gradient system, (cyclohexane/ethyl acetate): (95/5) to(70/30), afforded the title compound as a white solid (230 mg, 60%).mp=100-101° C. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.34 (s, 9H), 3.54(s, 3H), 4.09 (s, 4H), 5.24 (s, 2H), 6.45 (d, J=16.06 Hz, 1H), 6.77 (d,J=8.53 Hz, 1H), 7.28-7.53 (m, 10H), 7.70 (d, J=16.06 Hz, 1H), 7.79 (d,J=2.26 Hz, 1H).

Example 67 Methyl3-{4-[(5-tert-butyl-2-methoxyphenyl)carbonyl]phenyl}propanoate

3-{4-[2-(5-tert-butyl-2-methoxyphenyl)-1,3-dioxolan-2-yl]phenyl}propanoicacid was prepared according to example 38 starting from 166 mg of(3E)-4-{4-[2-(5-tert-butyl-2-methoxyphenyl)-1,3-dioxolan-2-yl]phenyl}but-3-en-2-one.3-{4-[2-(5-tert-butyl-2-methoxyphenyl)-1,3-dioxolan-2-yl]phenyl}propanoicacid was obtained as a mixture with3-{4-[(5-tert-butyl-2-methoxyphenyl)methyl]phenyl}propanoic acid (25%).It was used in the following reaction without any further purification.

To solution of the previous carboxylic acids mixture (175 mg 0.46 mmolregarding the highest MW, 1 eq.) in DCM (4 mL), were added methanol(100, 1.12 mmol, 6.8 eq.) and EDC.Cl (105 mg, 0.55 mmol, 1.2 mmol).After strirring 3 hours, the mixture was diluted in DCM (50 mL) andwashed with aqueous sat.NaHCO₃ (2×30 mL) and water (2×30 mL). Theorganic layer was dried over Ca₂SO₄ and concentrated. Purification ofthe crude by silica gel chromatography using the following gradientsystem, (cyclohexane/ethyl acetate): (93/7) to (40/60), afforded methyl3-{4-[2-(5-tert-butyl-2-methoxyphenyl)-1,3-dioxolan-2-yl]phenyl}propanoateas a mixture with methyl3-{4-[(5-tert-butyl-2-methoxy-phenyl)methyl]phenyl}propanoate. It wasused in the following step without any further purification.

Title compound was obtained according to example 3, starting from 64 mgof the previously obtained mixture. Purification of the crude by silicagel chromatography using the following gradient system,(cyclohexane/ethyl acetate): (100/0) to (60/40), afforded the titlecompound as a brown oil (32 mg). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm1.30 (s, 9H), 2.66 (d, J=7.78 Hz, 2H), 3.01 (t, J=7.68 Hz, 2H), 3.70 (s,3H), 3.67 (s, 3H), 6.92 (d, J=8.72 Hz, 1H), 7.26 (d, J=8.09 Hz, 2H) 7.34(d, J=2.30 Hz, 1H) 7.47 (dd, J=8.72, 2.30 Hz, 1H) 7.76 (d, J=8.09 Hz,2H). HRMS (TOF MS ES−) for C20H23O3− (M−H)− calcd. 311.1647, found311.1658.

Example 68 3-{4[(5-tert-butyl-2-methoxyphenyl)carbonyl]phenyl}propanoicacid

3-{4-[(5-tert-butyl-2-methoxyphenyl)carbonyl]phenyl}propanoic acid wasprepared according to example 3, starting from 30 mg of methyl3-{4-[(5-tert-butyl-2-methoxyphenyl)carbonyl]phenyl}propanoate. A yellowoil was obtained (28 mg, 98%). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm1.25-1.38 (m, 9H), 2.71 (t, J=7.72 Hz, 2H), 3.02 (t, J=7.72 Hz, 2H),3.70 (s, 3H), 6.92 (d, J=8.785 Hz, 1H), 7.23-7.30 (m, 2H), 7.35 (d,J=2.42 Hz, 1H), 7.47 (dd, J=8.75, 2.42 Hz, 1H), 7.77 (d, J=8.16 Hz, 2H).HRMS (TOF MS ES−) for C21H23O4− (M−H)− calcd. 339.1596, found 339.1611.

Example 69 methyl(2E)-3-{4-[5-(adamantan-1-yl)-2-methoxybenzoyl]phenyl}prop-2-enoate (a)4-(Adamantan-1-yl)phenol

Phenol (1.88 g, 0.02 mol) and 3.04 g (0.02 mol) of 1-adamantanol weredissolved in 10 mL of dichloromethane. To the resulting solution wasslowly added 1.1 mL (0.02 mol) of concentrated sulfuric acid (98%). Themixture was stirred overnight at room temperature, poured into water,neutralized with sodium bicarbonate, extracted with EtOAc, dried overMgSO₄, and evaporated. Recrystallization from cyclohexane provided 2.5 g(55%) of a white solid; M. p. 181-182° C. ¹H NMR (400 MHz, DMSO) δ 9.08(s, 1H), 7.12 (d, J=8.6 Hz, 2H), 6.67 (d, J=8.6 Hz, 2H), 2.02 (s, 3H),1.80 (s, 3H), 1.79 (s, 3H), 1.70 (s, 6H). ¹³C NMR (101 MHz, DMSO) δ154.93, 141.27, 125.37, 114.67, 42.91, 36.22, 34.91, 28.35.HRMS (TOF MSES−) for C16H19O− (M−H−) calcd. 227.1436, found 227.1433.

(b) 1-(4-Methoxyphenyl)adamantane

To a suspension of sodium hydride (60% in oil, 0.46 g, 10 mmol) in 10 mLof DMF was slowly added, while maintaining the temperature at 20° C.,2.28 g (10 mmol) of 69 (a). The mixture was stirred for 1 h at roomtemperature at which point CH3I (0.68 mL, 11 mmol) was added. Themixture was then stirred for 2 h at 20° C., poured into water, andextracted with Et₂O. After standard work-up followed by chromatography(cyclohexane), 1.426 g (59%) of 29 as a white solid was obtained. M. p.76-77° C.; Rf=0.34 (5% EtOAc:cyclohexane), ¹H NMR (400 MHz, CDCl3) δ7.28 (d, J=8.9 Hz, 1H), 6.86 (d, J=8.9 Hz, 1H), 3.79 (s, 3H), 2.08 (s,3H), 1.89 (s, 3H), 1.88 (s, 3H), 1.81-1.69 (m, 6H). ¹³C NMR (101 MHz,CDCl3) δ 157.32, 143.70, 125.76, 113.38, 55.19, 43.38, 36.79, 35.53,28.99.

(c)[5-(Adamantan-1-yl)-2-methoxyphenyl)](4-iodophenyl)methanone

Compound was prepared according to the procedure described by Boehm etal. (J. Med. Chem. 1994, 37, 2930-2941) from example 69 (b). Afterwork-up, the crude product was purified by chromatography to yield 69(c) as a yellow oil, 1.50 g (28%). Rf=0.60 (5% EtOAc:cyclohexane). ¹HNMR (400 MHz, CDCl₃) δ 7.78 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.4 Hz, 2H),7.46 (dd, J=8.7, 2.4 Hz, 1H), 7.35 (d, J=2.4 Hz, 1H), 6.93 (d, J=8.7 Hz,1H), 3.69 (s, 3H), 2.08 (s, 3H), 1.89 (s, 6H). 1.75 (q, J=12.1 Hz, 6H).¹³C NMR (101 MHz, CDCl3) δ 196.26, 155.35, 143.94, 137.57, 131.35,128.86, 127.72, 126.51, 111.30, 100.84, 55.77, 43.36, 36.79, 35.80,29.01. HRMS (TOF MS ES+) for C24H26IO2+ (MH+) calcd. 473.0978, found473.0981.

(d) Methyl(2E)-3-{4-[5-(adamantan-1-yl)-2-methoxybenzoyl]phenyl}prop-2-enoate

To a stirred solution of example 69 (c) (1.24 g, 2.63 mmol) and Et₃N(1098 uL, 7.89 mmol) was added 357 uL (3.94 mmol) of methyl acrylate.Palladium (II) acetate (12 mg) and (2-Tol)3P (64 mg) was added andheated at 100° C. for 3 hrs. The reaction mixture was allowed to cool tort, concentrated under reduced pressure and purified by chromatographyto yield a yellow solid, 0.59 g (52%). M. p. 135.5-137° C.; Rf=0.40 (15%EtOAc:cyclohexane). ¹H NMR (400 MHz, CDCl3) δ 7.82 (d, J=8.2 Hz, 2H),7.72 (d, J=16.0 Hz, 1H), 7.57 (d, J=8.2 Hz, 2H), 7.47 (dd, J=8.7, 2.4Hz, 1H), 7.36 (d, J=2.3 Hz, 1H), 6.94 (d, J=8.7 Hz, 1H), 6.52 (d, J=16.0Hz, 1H), 3.82 (s, 3H), 3.69 (s, 3H), 2.09 (s, 3H), 1.90 (s, 6H), 1.77(s, 3H), 1.74 (s, 3H). ¹³C NMR (101 MHz, CDCl3) δ 196.27, 167.17,155.42, 143.99, 143.81, 139.40, 138.43, 130.45, 128.84, 128.06, 127.93,126.54, 120.15, 111.35, 55.81, 52.00, 43.40, 36.83, 35.85, 29.05. HRMS(TOF MS ES+) for C28H31O4+ (MH+) calcd. 431.2222, found 431:2227.

Example 70 Methyl(2E)-3-(4-{2-[5-(adamantan-1-yl)-2-methoxyphenyl]-1,3-dioxolan-2-yl}phenyl)prop-2-enoate

Example 69 (200 mg, 0.46 mmol) was treated with ethylene glycol (2 mL)and a catalytic amount of pTsOH (20 mg) in toluene (10 mL) at 145° C.overnight using a Dean Stark trap according to a modified procedure ofDawson et al. 8 After cooling to rt, it was washed with saturatedNaHCO₃(aq.), brine, dried over MgSO₄ and concentrated under reducedpressure. The residue was purified using Biotage to yield a white solid,112 mg (64%, 40 mg of starting material recovered). M.p. 163-165° C.;Rf=0.34(15% EtOAc:cyclohexane). ¹H NMR (400 MHz, CDCl3) δ 7.77 (d, J=2.5Hz, 1H), 7.67 (d, J=16.0 Hz, 1H), 7.49 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.4Hz, 2H), 7.28 (d, J=8.5, 2.5 Hz, 1H), 6.79 (d, J=8.6 Hz, 1H), 6.40 (d,J=16.0 Hz, 1H), 4.09 (s, 4H), 3.79 (s, 3H), 3.55 (s, 3H), 2.11 (s, 3H),1.94 (s, 3), 1.93 (s, 3H), 1.78 (s, 6H). ¹³C NMR (101 MHz, CDCl3) δ167.65, 154.99, 145.17, 144.88, 143.45, 133.70, 129.04, 127.58, 126.82,126.21, 123.25, 117.69, 112.28, 108.96, 65.28, 56.05, 51.80, 43.58,36.96, 35.88, 29.18. HRMS (TOF MS ES+) for C30H35O5+ (MH+) calcd.475.2484, found 475.2484.

Example 71(2E)-3-(4-{2-[5-(adamantan-1-yl)-2-methoxyphenyl]-1,3-dioxolan-2-yl}phenyl)prop-2-enoicacid

To a solution of the example 70 (140 mg, 0.29 mmol) in anhydrous THF (5mL) was added aqueous LiOH (1.0 mL, 1.0 N) dropwise. The reactionmixture was stirred at 75° C. for 3 hrs. The reaction was then cooled(0° C.), acidified to pH 2 with 1.0 N HCl, and extracted with EtOAc(3×15 mL). The combined organic phases were dried (anhydrous Na2SO4) andconcentrated in vacuo to afford a thick colorless oil. The resultant oilwas purified on a 30 g Biotage ZIP cartridge and eluted with 0-60%EtOAc:cyclo-hexane+0.1% HOAc gradient to provide a white solid (129 mg,96%). M.p. 238-240° C.; Rf=0.40 (60% EtOAc:cyclo-hexane+0.1% HOAc), ¹HNMR (400 MHz, CDCl3) δ 7.78 (d, J=2.5 Hz, 1H), 7.76 (d, J=16.2 Hz, 1H),7.51 (d, J=8.3 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.28 (dd, J=8.6, 2.5 Hz,1H), 6.79 (d, J=8.6 Hz, 1H), 6.41 (d, J=15.9 Hz, 1H), 4.10 (s, 4H), 3.55(s, 3H), 2.11 (s, 3H), 1.94 (s, 3H), 1.94 (s, 3H), 1.78 (s, 6H). ¹³C NMR(101 MHz, CDCl3) δ 171.86, 154.97, 147.06, 145.66, 143.46, 133.36,128.97, 127.88, 126.90, 126.26, 123.24, 117.02, 112.27, 108.93, 65.29,56.03, 43.58, 36.96, 35.89, 29.18. HRMS (TOF MS ES+) for C29H35O5+ (MH+)calcd. 463.2484, found 463.2484.

Example 723-(4-{2-[5-(adamantan-1-yl)-2-methoxyphenyl]-1,3-dioxolan-2-yl}phenyl)propanoicacid

Example 71 was hydrogenated according to the general procedure for theformation of example 38 to provide a white solid 93 mg (86%) afterchromatography; m. p. 173-175° C. ¹H NMR (400 MHz, CDCl3) δ 7.76 (d,J=2.5 Hz, 1H), 7.39 (d, J=8.2 Hz, 2H), 7.26 (d, J=8.5, 2.5 Hz, 1H), 7.11(d, J=8.2 Hz, 2H), 6.79 (d, J=8.6 Hz, 1H), 4.08 (ddd, J=6.3, 3.4, 1.9Hz, 4H), 3.54 (s, 3H), 2.92 (t, J=7.8 Hz, 2H), 2.64 (t, J=7.8 Hz, 2H),2.10 (s, 3H), 1.93 (s, 3H), 1.93 (s, 3H), 1.78 (s, 6H). ¹³C NMR (101MHz, CDCl3) δ 178.29, 155.12, 143.33, 140.85, 139.49, 129.51, 127.60,126.46, 125.94, 123.37, 112.40, 109.26, 65.17, 56.12, 43.57, 36.97,35.86, 35.56, 30.46, 29.18. HRMS (TOF MS ES+) for C29H35O5+ (MH+) calcd.463.2484, found 463.2484.

Example 73 Methyl3-(4-{2-5-(adamantan-1-yl)-2-methoxyphenyl]-1,3-dioxolan-2-yl}phenyl)propanoate

Example 73 was prepared from example 70 by hydrogenation under Pd—Ccatalysis using the general procedure (example 38) to provide a whitesolid, 260 mg (85%). M. p. 112-113° C.; R_(f)=0.45 (15%EtOAc:cyclohexane). ¹H NMR (400 MHz, CDCl₃) δ 7.76 (d, J=2.5 Hz, 1H),7.38 (d, J=8.2 Hz, 2H), 7.26 (dd, J=8.5, 2.6 Hz, 1H), 7.10 (d, J=8.2 Hz,2H), 6.79 (d, J=8.6 Hz, 1H), 4.17-3.99 (m, 4H), 3.65 (s, 3H), 3.55 (s,3H), 2.91 (t, J=7.9 Hz, 2H), 2.59 (t, J=7.9 Hz, 2H), 2.10 (s, 3H), 1.93(s, 3H), 1.93 (s, 3H), 1.86-1.69 (m, 6H). ¹³C NMR (101 MHz, CDCl₂) δ173.51, 155.12, 143.32, 140.71, 139.83, 129.52, 127.60, 126.40, 125.92,123.37, 112.38, 109.27, 65.16, 56.13, 51.71, 43.56, 36.96, 35.85, 35.81,30.78, 29.17. HRMS (TOF MS ES+) for C₃₀H₃₇O₅ ⁺ (MH+) calcd. 477.2641,found 477.2643.

Example 74 Methyl3-{4-[3-(adamantan-1-yl)-2-methoxybenzoyl]phenyl}propanoate

A mixture of example 73 (146 mg, 0.31 mmol) and iodine (100 mg, 0.39mmol) in acetone (6 mL, reagent ACS, 0.2% H₂O) was stirred for 3 hrsunder reflux according to the reported method for example 45. Afterwork-up and purification on a Biotage 45 g ZIP cartridge using 0-15%EtOAc:cyclohexane gradient, a brown oil (120 mg, 91%) was obtained;R_(f)=0.40 (15% EtOAc:cyclohexane). ¹H NMR (400 MHz, CDCl₃) δ 7.76 (d,J=8.2 Hz, 2H), 7.44 (dd, J=8.7, 2.4 Hz, 1H), 7.32 (d, J=2.4 Hz, 1H),7.26 (d, J=8.0 Hz,2H), 6.93 (d, J=8.7 Hz, 1H), 3.70 (s, 3H), 3.67 (s,3H), 3.01 (t, J=7.7 Hz, 2H), 2.66 (t, J=7.7 Hz, 2H), 2.08 (s, 3H), 1.89(s, 3H), 1.88 (s, 3H), 1.75 (q, J=12.1 Hz, 6H), ¹³C NMR (101 MHz, CDCl₃)δ 196.63, 173.15, 155.24, 146.03, 143.77, 136.33, 130.46, 128.55,128.30, 128.25, 126.26, 111.30, 55.87, 51.85, 43.39, 36.84, 35.81,35.29, 31.07, 29.05. HRMS (TOF MS ES+) for C₂₈H₃₃O₄ ⁺ (MH+) calcd.433.2379, found 433.2381.

Example 75 Methyl3-(4-{2-[5-(adamantan-1-yl)-2-methoxyphenyl]-1,3-dithiolan-2-yl}phenyl)propanoate

Prepared according to the reported procedure for example 48. To asolution of the keto ester (117 mg, 0.27 mmol) in CR₂Cl₂ (5 mL) at rtunder argon was added a solution of the (CH₂SH)₂ (35 μL, 0.41 mmol)followed by BF₃.Et₂0 (52 μL, 0.41 mmol). The resulting mixture wasstirred at rt overnight. The reaction was quenched by pouring themixture into saturated NaHCO₃, and the mixture was extracted with 20 mLCH₂Cl₂. The combined organic layers were dried (MgSO₄) and concentratedto afford a solid. Flash chromatography (15% CH₂Cl₂:cyclohexane) yieldeda yellow solid, 106 mg (77%). M. p. 127-1.28° C.; R_(f)=0.50 (15%EtOAc:cyclohexane). ¹H NMR (400 MHz, CDCl3) δ 8.11 (d, J=2.3 Hz, 1H),7.39 (d, J=8.2 Hz, 2H), 7.25 (dd, J=8.3, 2.4 Hz, 1H), 7.02 (d, J=8.1 Hz,2H), 6.79 (d, J=8.5 Hz, 1H), 3.65 (s, 3H), 3.50 (s, 3H), 3.44 (dt,J=10.0, 7.5 Hz, 2H), 3.31 (dt, J=11.8, 7.2 Hz, 2H), 2.89 (t, J=7.9 Hz,2H), 2.58 (t, J=7.9 Hz, 2H), 2.12 (s, 3H), 1.96 (s, 3H), 1.96 (s, 3H),1.79 (s, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 173.55, 154.68, 143.39, 143.34,138.73, 133.36, 127.59, 127.03, 125.03, 123.78, 112.49, 74.73, 55.88,51.71, 43.64, 40.41, 36.98, 36.05, 35.71, 30.61, 29.20. HRMS (TOF MSEST) for C₃₀H₃₇O₃S₂ ⁺ (MH+) calcd. 509.2184, found 509.2184.

Example 763-(4-{2-[5-(adamantan-1-yl)-2-methoxyphenyl]-1,3-dithiolan-2-yl}phenyl)propanoicacid

Example 75 was hydrolyzed according to example 3 to yield a white solid,49 mg (55%). ¹H NMR (400 MHz, CDCl₃) δ 8.11 (d, J=2.4 Hz, 1H), 7.40 (d,J=8.2 Hz, 2H), 7.25 (dd, J=8.3, 2.4 Hz, 1H), 7.03 (d, J=8.2 Hz, 2H),6.79 (d, J=8.5 Hz, 1H), 3.50 (s, 3H), 3.48-3.39 (m, 2H), 3.36-3.26 (m,2H), 2.90 (t, J=7.8 Hz, 2H), 2.63 (t, J=7.8 Hz, 2H), 2.12 (s, 3H), 1.96(s, 3H), 1.96 (s, 3H), 1.85-1.71 (m, 6H). ¹³C NMR (101 MHz, CDCl₃) δ178.06, 154.68, 143.54, 143.34, 138.38, 133.35, 127.59, 127.08, 125.05,123.77, 112.50, 74.71, 55.89, 43.65, 40.42, 36.98, 36.05, 35.40, 30.27,29.20. HRMS (TOF MS ES+) for C₂₉H₃₅O₃S₂ ⁺(MH+) calcd. 495.2028, found495.2030.

Example 77 Methyl(2E)-3-{4-[5-(adamantan-1yl)-2-hydroxybenzoyl]phenyl}prop-2-enoate (a)[5-adamantan-1-yl)-2-hydroxyphenyl)](4-iodophenyl)methanone

The compound was obtained following the procedure used for Example 48using example 69 (c). After work-up, the crude product was purified bychromatography and recrystallized from EtOAc to yield example 77 (a) asa yellow solid, 1.09 g (21%). M. p. 186-187° C.; R_(f)=0.50 (5%EtOAe:cyclohexane). ¹H NMR (400 MHz, CDCl₃) δ 11.72 (s, 1H), 7.89 (d,J=8.4 Hz, 2H), 7.57 (dd, J=8.8, 2.4 Hz, 1H), 7.47 (d, J=2.4 Hz, 1H),7.43 (d, J=8.4 Hz, 2H), 7.03 (d, J=8.8 Hz, 1H), 2.08 (s, 3H), 1.80 (s,3H), 1.80 (s, 3H), 1.76 (s, 3H), 1.72 (s, 3H). ¹³C NMR (101 MHz, CDCl₃)δ 200.72, 161.24, 142.04, 137.76, 137.59, 134.05, 130.93, 129.17,118.37, 118.24, 99.50, 43.25, 36.69, 35.68, 28.92. HRMS (TOF MS ES+) forC₂₃H₂₄IO₂ ⁺ (MH+) calcd. 459.0821, found 459.0818.

(b) Methyl(2E)-3-{4-[5-(adamantan-1-yl)-2-hydroxybenzoyl]phenyl}prop-2-enoate

Prepared according to the procedure of 42 (c) to yield a yellow solidafter purification by chromatography, 0.85 g (94%). M. p. 158-160° C.;R_(f)=0.45 (15% EtOAc:cyclohexane). ¹H NMR (400 MHz, CDCl₃) δ 11.78 (s,1H), 7.77 (d, J=16.1 Hz, 1H), 7.73 (d, J=8.3 Hz, 2H), 7.68 (d, J=8.3 Hz,2H), 7.58 (dd, J=8.8, 2.4 Hz, 1H), 7.49 (d, J=2.4 Hz, 1H), 7.04 (d,J=8.8 Hz, 1H), 6.58 (d, J=16.0 Hz, 1H), 3.84 (s, 3H), 2.07 (s, 3H), 1.80(s, 3H), 1.80 (s, 3H), 1.76 (d, J=13.4 Hz, 3H), 1.69 (d, J=12.0 Hz, 3H).¹³C NMR (101 MHz, CDCl₃) δ 200.79, 167.10, 161.28, 143.54, 142.00,139.54, 137.84, 134.01, 130.02, 129.30, 128.03, 120.34, 118.54, 118.21,52.05, 43.25, 36.70, 35.68, 28.93. HRMS (TOF MS ES+) for C₂₇H₂₇H₂₉O₄ ⁺(MH+) calcd. 417.2066, found 417.2068.

Example 78 Methyl3-(4-{[5-(adamantan-1-yl)-2-hydroxyphenyl]methyl}phenyl)-propanoate

Example 7 7 was hydrogenated using the same procedure as for theformation of example 38 to provide 90 mg (82%) of a white solid. M, p.102-103° C.; R_(f)=0.25 (10% EtOAc:cyclohexane). ¹H NMR (400 MHz, CDCl₃)δ 7.19-7.01 (m, 6H), 6.73 (d, J=8.0 Hz, 1H), 4.53 (s, 1H), 3.96 (s, 2H),3.66 (s, 3H), 2.91 (t, J=7.8 Hz, 2H), 2,60 (t, J=7.8 Hz, 2H), 2.07 (s,3H), 1.87 (s, 6H), 1.75 (q, J=12.3 Hz, 6H). ¹³C NMR (101 MHz, CDCl₃) δ173.56, 151.66, 144.26, 138.57, 138.17, 128.81, 128.67, 127.75, 126.23,124.33, 115.51, 51.76, 43.56, 36.96, 36.72, 35.85, 35.71, 30.68, 29.16.HRMS (TOF MS ES+) for C₂₇H₃₃O₃ ⁺ (MH+) calcd. 405.2430, found 405.2430.

Example 793-(4-{[5-(adamantan-1-yl)-2-hydroxyphenyl]methyl}phenyl)propanoic acid

Example 78 was hydrolyzed following the same procedure as for thepreparation of example 3 to obtain a yellow oil, 80 mg (89%). R_(f)=0.40(50% EtOAc;cyclohexane). ¹H NMR (400 MHz, CDCl₃) δ 7.13 (Aromatic, 6H),6.73 (d, J=8.1 Hz, 1H), 3.96 (s, 2H), 2.92 (t, 7.7 Hz, 2H), 2.65 (t,J=7.7 Hz, 2H), 2.07 (s, 3H), 1.87 (s, 3H), 1.87 (s, 3H), 1.75 (q, J=12.3Hz, 7H), ¹³C NMR (101 MHz, CDCl₃) δ 178.18, 151.63, 144.28, 138.32,138.21, 128.86, 128.66, 127.77, 126.21, 124.34, 115.51, 43.56, 36.95,36.71, 35.71, 30.34, 29.15. HRMS (TOF MS ES+) for C₅₂H₆₁O₆ ⁺ (2MH+)calcd. 781.4468, found 781.4467.

Example 80 Characterization of Inhibitors of Cytochrome P450 26B1

9-cis-RA, acitretin,4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carboxamido]benzoicacid (AM 580) and NADPH were purchased from Sigma-Aldrich (St. Louis,Mo.).(R)—N-[4-[2-ethyl-1-(1H-1,2,4-triazol-1-yl)butyl]phenyl]-2-benzo-thiazolamine(R115866, talarozole) and R116010 were gifts from Johnson & Johnson(Beerse, Belgium).4-[(E)-2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoicacid (TTNPB),6-[2-(3,4-Dihydro-4,4-dimethyl-2H-1-benzothiopyran-6-yl)ethynyl]-3-pyridinecarboxylicacid ethyl ester (Tazarotene),4-[2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)ethynyl)-benzoicacid (EC23),4-[[(2,3-Dihydro-1,1,3,3-tetramethyl-2-oxo-1H-inden-5-yl)carbonyl]amino]benzoicacid (BMS753),3-Fluoro-4-[[2-hydroxy-2-(5,5,8,8-tetramethyl-5,6,7,8,-tetrahydro-2-naphthalenyl)acetyl]amino]-benzoicacid (BMS961), and4-[[(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)amino]-carbonyl]benzoicacid (AM80) and liarozole were purchased from Tocris Bioscience(Ellisville, Mo.). 4-OH-9-cis-RA was purchased from Toronto ResearchChemicals Inc. (North York, ON, Canada). All solvents used were HPLCgrade or higher and were purchased from EMD Chemicals (Gibbstown, N.J.),Mallinckrodt Baker, Inc. (Phillipsburg, N.J.), or Thermo FisherScientific (Waltham, Mass.).

Compound 1 was obtained in 73% yield by reacting2-Bromo-1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethan-1-onewith Methyl-4-hydroxybenzoate in the presence of K₂CO₃ in Methyl ethylketone under microwave conditions. Compound B was obtained aftersaponification of the methyl ester of compound A using sodium hydroxide.Reaction of B with hydroxylaminehydrochloride in MeOH under refluxyielded 2 isomers of the corresponding oximes, E-(E) and Z-(F).Compounds E and F yielded crystals of suitable quality for X-raydiffraction by slow evaporation of ethyl acetate/heptane solutions.These crystals were used to confirm the structures using X-ray datacollected at 90 K, with Cu Kα radiation (λ=1.54178 Å) on a Balker KappaApex-II diffractometer. Crystals of E are triclinic, space group P-1with Z=2, R=0.036. Crystals of F are monoclinic, space group P2₁/c withZ=4. R=0.065. There is a conformational disorder of the six-memberedring carrying the four methyl groups. The Z-isomer was furtherhydrolyzed under basic conditions to provide the desired product D.Reduction of compound A using sodium borohydride followed bysaponification yielded compound C. Tazarotene was hydrolyzed by refluxin K₂CO₃/MeOH to yield the corresponding acid in excellent yield.

Incubation Conditions for CYP26A1 and CYP26B1 and HPLC Analysis of RAIsomers and Metabolites

CYP26A1 and CYP26B1 were expressed in Sf9 cells and used as microsomalfractions supplemented with rat P450 reductase expressed in Escherichiacoli as described previously. Incubations were performed with 5 pmol ofP450 (CYP26A1 or CYP26B1) and 10 pmol of P450 reductase. The purifiedrat reductase was added to CYP26A1 or CYP26B1 microsomes, and allowed toincorporate into the membrane for 10 min at room temperature. The finalvolume of each incubation sample was then brought to 1 ml by adding 100mM potassium phosphate (KPi) buffer, pH 7.4, 9-cis-RA, and, whenappropriate, inhibitor or solvent. Compounds were dissolved in methanolor dimethyl sulfoxide, and final solvent amounts in the incubations werekept at 1%. The samples were preincubated for 5 min at 37° C. before thereaction was initiated with NADPH (final concentration 1 mM). Incubationtimes were 1 minute and 5 minutes for CYP26A1 and CYP26B1 incubationsrespectively.

To determine whether the RA isomer 9-cis-RA is a substrate of CYP26B1,9-cis-RA was incubated with CYP26B1. The formation of 9-cis-4-OH-RA byCYP26B1 was measured by HPLC as described previously for CYP26A1.Product formation was linear from 1 minute to 8 minutes. The K_(m) andV_(max) of 9-cis-RA hydroxylation by CYP26B1 was determined byincubating 8 different concentrations of 9-cis-RA between 50 nM and 1000nM with CYP26B1. Five minutes after reactions were initiated with NADPHthe reactions were quenched with 5 ml of ethyl acetate, acitretin wasadded as an internal standard, samples extracted, evaporated to dryness,reconstituted in methanol and analyzed by HPLC as described previously.A standard curve of 9-cis-4-OH-RA was used to quantify product formationby analysis of the peak area of the primary metabolite on an HPLC. TheMichaelis-Menten equation was fit to the data using GraphPad Prism(GraphPad Software Inc., San Diego, Calif.), and the K_(m) and V_(max)values were obtained from this fit. 9-cis-RA was then used at 100 nMconcentration as the substrate for subsequent assays of inhibitorpotency.

CYP26A1 and CYP26B1 Inhibition Assay

Eighteen compounds were tested as potential inhibitors of CYP26A1 andCYP26B1. The formation of 9-cis-4-OH-RA metabolite was monitored and thepercent activity remaining in the presence of the inhibitor incomparison to the solvent only control was quantified. For IC₅₀determination, 6-8 concentrations of the inhibitor spanning below andabove the predicted IC₅₀ were tested, and each concentration wasanalyzed in triplicate. The IC₅₀ values were determined by nonlinearregression using GraphPad Prism, according to equation 1:

$\begin{matrix}{{100{\% \cdot \frac{V_{i}}{V}}} = {{{\left( \frac{V_{i}}{V} \right)_{\min} \cdot 100}\%} + \frac{\left( {\left( {V_{i}/V} \right)_{\max} - {{\left( {V_{i}/V} \right)_{\min} \cdot 100}\%}} \right)}{\left( {1 + 10^{({I - {logIC}_{50}})}} \right)}}} & (1)\end{matrix}$

in which 100% *(V_(i)/V) is the percentage of activity remaining at agiven inhibitor (I) concentration, (V_(i)/V)_(max)*100% is the fittedmaximum percentage activity remaining, and (V_(i)/V)_(min)*100% is theminimum percentage activity remaining. For compounds with IC₅₀ valuesless than 100 nM, all fits were corrected for inhibitor depletion, andthe K_(d) was determined using the Morrison equation as describedpreviously according to equation 2:

$\begin{matrix}{\lbrack{EI}\rbrack = \frac{\lbrack E\rbrack + \lbrack I\rbrack + K_{d} - \sqrt{\left( {\lbrack E\rbrack + \lbrack I\rbrack + K_{d}} \right)^{2} - {{4\lbrack E\rbrack}\lbrack I\rbrack}}}{2}} & (2)\end{matrix}$

in which K_(d) is the affinity constant of the inhibitor, [I] is theconcentration of inhibitor, [E] is the concentration of enzyme, and [EI]is the concentration of the enzyme-inhibitor complex.

Inhibition Assay for CYP2B8, CYP2C9 and CYP3A4

Compounds were assessed for inhibition (IC₅₀, n=2) of CYP2C8, CYP2C9 andCYP3A4 in pooled human liver microsomes using selective probe substratesat their previously determined K_(m) values (CYP2C8: paclitaxel, 4 μM;CYP2C9: diclofenac, 5 μM; CYP3A4: midazolam, 0.5 μM). Incubationscontained 0.1 mg/mL human liver microsomes, 3 mM MgCl2, probe substrateand various concentrations of inhibitor (12-point IC₅₀ curve) in 100 mMpotassium phosphate buffer (pH 7.4). Concentrations of organic solventswere kept to <1% (v/v). All incubations were pre-incubated at 37° C. for5 minutes prior to addition of 1 mM NADPH (final concentration).Incubations were stopped after 5 (CYP3A4) or 15 minutes (CYP2C8 andCYP2C9) with one volume (v/v) of ice-cold acetonitrile containing 0.1 μMtolbutamide as an internal standard. All samples were vortexed andcentrifuged prior to LC-MS/MS analysis.

Detection of 6-hydroxypaclitaxel, 4-hydroxydiclofenac or1′-hydroxymidazolam was achieved using a Gemini C18 2.0×30 mm 5 column(Phenomenex, Torrance, Calif.). Gradient elution (flow rate=500 μL/min)carried out using a mobile phase system consisting of (A) 5 mM ammoniumformate with 0.1% formic acid and (B) acetonitrile with 0.1% formicacid. HPLC flow was diverted from the MS/MS system for the first 20seconds to remove any non-volatile salts. Generic MS parameters includedthe curtain gas (10 arbitrary units), CAD gas (medium), ionspray voltage(4500 V), source temperature (450° C.) and ion source gas 1 and gas 2(40 arbitrary units, each). Interface heaters were kept on for allanalytes. Probe substrate mass transitions were identical to previouslypublished methods. Briefly, the LC-MS/MS system utilized was comprisedof an Applied Biosystems 4000 Q-Trap equipped with an electrosprayionization source (Applied Biosystems, Foster City, Calif.). The MS/MSsystem was coupled to two LC-20AD pumps with an in-line CBM-20Acontroller and DGU-20A₅ solvent &gasser (shinadzu, Columbia, Md.) and aLEAP CTC HTS PAL autosampler equipped with a dual-solvent self-washingsystem (CTC Analytics, Carrboro, N.C.). An injection volume of 20 μL wasused for all analyses. Standard curves and mass spectrometry data werefit using Analyst (version 1.4; Applied Biosystems, Foster City,Calif.). Analysis of IC₅₀ data was performed as described above forCYP26 inhibition assays.

CYP26B1Homology Model.

The amino acid sequence of human CYP26B1 was obtained from the NCBIprotein server (UniProtKB/Swiss-Prot Accession Number: Q9NR63) and usedto construct a three-dimensional homology model of CYP26B1 using Prime(Schrodinger LLC, New York). The crystal structure of cyanobacterialCYP120A1 with atRA bound in the active site (pdb 2VE3) was used as thetemplate for model based on sequence similarity between the two proteins(34% sequence identity; 54% positive sequence coverage). Proteinstructure alignment between the newly constructed homology model and acrystal structure of CYP3A4 with ketoconazole bound (pdb 2V0M) was usedto position the heme prosthetic group within the active site of CYP26B1.The heme iron was ligated to Cys441 of CYP26B1 and the entire proteinstructure subject to energy minimization using the OPLS_2005 force fieldconstraints within the MacroModel module (Schrodinger LLC, New York).Glide (Schrodinger LLC, New York) was then used to define a 14×14×14 Åreceptor grid centered approximately 2 Å above the heme iron.Ramachandran plots and visual inspection were used to assess thestructural plausibility of the homology model. Glide was also used todock ligands within the defined active site of the CYP26B1 homologymodel using the ligand docking algorithm such that the center of eachligand was located within the defined grid. Prior to docking, ligandswere prepared using the OPLS_2005 force field constraints within LigPrep(Schrodinger LLC, New York). Final docking poses were evaluated usingGlideScore and eModel parameters.

Validation of CYP26B1 Inhibition Assay

To determine the inhibition of CYP26A1, a method was previouslydeveloped using recombinant CYP26A1 microsomes and 9-cis-RA as asubstrate. To allow characterization of inhibition of CYP26B1, 9-cis-RAturnover by recombinant CYP26B1 was tested. 9-cis-RA was shown to be asubstrate of CYP26B1 and metabolite formation was NADPH dependent (FIG.1A). A single metabolite was detected from 9-cis-RA and the retentiontime of this metabolite was compared to synthetic 9-cis-4-OH-RA (FIG.1A). The similar retention time suggests that the metabolite formed is9-cis-4-OH-RA, The K_(m) and V_(max) for 9-cis-4-OH-RA formation byCYP26B1 were of 555 nM and 3.6 pmol/min/pmol P450, respectivelyresulting in an intrinsic clearance of 6.5 μL/min (FIG. 1B). Based onthe K_(m) value, all potential inhibitors of CYP26B1 were evaluated at asubstrate concentration of 100 nM (concentration <<K_(m) to increasesensitivity and decrease the dependence of IC₅₀ values on inhibitionmechanism). 9-cis-RA was used as the probe substrate for inhibitionscreening instead of atRA since it has a 50-fold greater K_(m) than atRAfor CYP26B1 (555 nM versus 19 nM), allowing incubations under linear,steady-state conditions. In addition, only a single metabolite is formedfrom 9-cis-RA by CYP26B1 and no subsequent sequential metabolism wasobserved.

Characterization of CYP 26 Isoform Selectivity of Known Azole Inhibitorsof RA Metabolism

The inhibition of CYP26A1 and CYP26B1 known azole inhibitors of atRAmetabolism (liarozole, ketoconazole, Talarozole and R116010) was testedusing recombinant CYP26A1 and CYP26B1 insect cell microsomes. The IC₅₀values are summarized in Table 1 and FIG. 2.

TABLE 1 IC₅₀ values for CYP Panel with Azole inhibitors CYP26A1 CYP26B1IC₅₀ nM IC₅₀ nM CYP26A1/ CYP2C8 CYP2C9 CYP3A4 Structure 95% CI 95% CICYP26B1 IC₅₀ nM IC₅₀ nM IC₅₀ nM

1900  1500-2300  18 13-27 106 480 1,630 10,000

660  370-1.2  140  34-560 5 1,560 2,570 <20

    5.1^(a,b) 3.4-6.8      0.46^(a) 0.069-0.85  11 220 680 470

    4.3^(a,b) 2.8-5.8      3.1^(a) 2.5-3.7 1 1,760 5,760 120 ^(a)K_(s)determined using Equation, Equation 2, ^(b)data from Thatcher, et al.Mol Pharmacol 2011, 80 (2), 228-39.

All four azole inhibitors also inhibited at least one drug metabolizingP450 potently (Table 1), but no correlation was observed betweeninhibitory potency of either CYP26 enzyme and inhibition of specificdrug metabolizing P450s. Liarozole inhibited CYP2C8 potently and was aweak inhibitor of CYP2C9 and CYP3A4. R116010 and ketoconazole werepotent CYP3A4 inhibitors and weak (IC₅₀>1 μM) inhibitors of CYP2C9 andCYP2C8. Talarozole inhibited all three drug metabolizing P450 enzymeswith nanomolar affinity.

In addition to inhibiting CYP26s, liarozole also inhibits othercytochromes involved in the biosynthetic pathways of testicular, ovarianand adrenal steroids (Berth-Jones J, et al. Treatment of psoriasis withoral liarozole: a dose-ranging study. British Journal of Dermatology.2000; 143(6):1170-6; Bruynseels J, et al. R 75251, a new inhibitor ofsteroid biosynthesis. The Prostate. 1990; 16(4):345-57.) The results ofa recent study do not support the assumption that pituitary compensationwill compensate for the decrease on steroid biosynthesis induced byazole-containing RAMBA (Woerdeman; J, et al. In Young Men, a ModerateInhibition of Testosterone Synthesis Capacity is Only Partly Compensatedby Increased Activity of the Pituitary and the Hypothalamus. ClinEndocrinol. 2010; 72(3):76-80.)

Inhibition of CYP26B1 and CYP26A1 by RAR Agonists

A series of commercially available RAR agonists were tested for CYP26A1and CYP26B1 inhibition due to their similarity with atRA in polarity,size, charge and 3D space. Six new structural analogs of the tested RARagonists were also synthesized to further evaluate the structuralrequirements of selective and potent CYP26A1 and CYP26B1 inhibition andpossible hydrogen bonding interactions within CYP26A1 and CYP26B1 activesite. The IC₅₀ values are summarized in Table 2 and FIGS. 3 and 4.

TABLE 2 IC₅₀ values for RAR agonists containing a carboxylic acid withCYP26A1 and CYP26B1 CYP26A1 CYP26B1 CYP26A1/ Structure IC₅₀ μM IC₅₀ μMCYP26B1

12   8.1-18 6.6 2.3-19  1.8

5.6 3.0-10 2.2 1.4-3.2 2.5

  3.7^(a) 1.4-9.8 3.4 2.2-5.2 1.1

4.0 2.5-6.3  0.93 0.61-1.4  4

2.8 1.7-4.8 1.4 0.77-2.6  2

3.5 2.2-5.6 1.4 0.40-4.8  3

18   4.4-76  28   21-37 0.6

14   9.6-20  31   15-63 0.5

6.1 3.2-12   0.13 0.090-0.19  47

8.3 4.0-17   0.94 0.44-2.0  9

ND^(a)  2.3^(b) 1.0-5.3 NA

ND^(c)  2.1^(d) 1.0-4.9

12   63-22 1.5 0.96-2.2  8

8.5 4.8-15  1.1 0.70-1.8  7 ^(a)Maximum 15% inhibition observed at 100μM ^(b)Only partial inhibition obtained, maximum inhibition was 54%^(c)Maximum 15% inhibition observed at 100 μM ^(d)Only partialinhibition obtained, maximum inhibition was 51%

The data shown here suggests that synthetic retinoids can bind toCYP26A1 and CYP26B1 but have variable potency as CYP26 inhibitors.

Example 81 Characterization of Inhibitors of Cytochrome P450 26A1

Compounds of the disclosure were tested as potential inhibitors ofCYP26A1 and CYP26B1. The conditions for IC₅₀ experiments along with themethods of data analysis are the same as described in Example 80. Theresults are shown in Tables 3, 4, and 5.

TABLE 3 Inhibitors for CYP26A1 selective inhibition Inhibitor CYP26A1CYP2681

12.3 4.0

3.3 14.2

0.061 1.03

TABLE 4 Acidic compounds designed to target CYP26A1 selective inhibitionInhibitor CYP26A1 CYP26B1

>25 >25

7.78 12.6

1.28 1.09

1.63 0.53

0.109 1.03

0.061 1.03

TABLE 5 Compound of the disclosure as inhibitors of CYP26A1 and CYP26B1CYP26A1 CYP26B1 Structure μM μM CYP3A4

0.66 0.14

1.9 0.018

0.516

0.314 0.302

>25 >25

0.729 0.087

0.232 0.095

0.051 0.051 24

1.752 0.108 2.4

0.34 14.5 50

0.006 4.4

0.269 0.684

>10 1.66

0.239 >10

0.0051 4.60E- 04

The earliest compounds designed to inhibit the metabolism of atRA,ketoconazole, liarozole and talarozole, all were shown to increase theconcentration of atRA in vivo in animal models, which agrees with themicrosomal inhibition of atRA metabolism that was found in both ourrecombinantly expressed protein prepared as microsomes, as well asprevious reports containing microsomal extracts that had been made fromcell lines induced to express GYP26A1. In many of the experiments thathave taken place to induce apoptosis or inhibit metabolism with smallmolecules, the consideration for the presence of both enyzmes, CYP26A1and CYP26B1, is not taken into consideration. There are also manytissues that have been profiled for protein content and found to haveequal amounts of either isozyme. The repetition of two enzymes that havevery similar functions is an interesting phenomenon and selectiveinhibition of either enzyme will help to characterize whether there areany differences in function between the two proteins, or whether theyare redundant in function in an adult.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be incorporated within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated herein by referencefor all purposes.

We claim:
 1. A compound of the formula (I):

or a pharmaceutically acceptable salt thereof, wherein A represents aryloptionally substituted with one, two, three, or four groups that areeach independently halogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl,—NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —OH, C₁-C₆ alkoxy, and C₁-C₆haloalkoxy; X is a bond, —CH₂—, —CHR⁵—, —C═CHR⁴—, —NR⁴—, —N═O—R⁴, —O—,—S—, —SO—, —SO₂—, —C(O)—, or —C(NR⁴)—, or X is of formula

wherein each n is independently 1, 2, or 3; each R⁴ is independentlyhydrogen or C₁₋₆ alkyl; R⁵ is independently hydrogen, C₁₋₆ alkyl, or—OR⁶, where R⁶ is selected from the group consisting of hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₂ cycloalkyl, heterocyclyl, aryl,arylC₁₋₆ alkyl, heteroaryl, or heteroarylC₁₋₆ alkyl; Y is C₁₋₆ alkylene,C₂₋₆ alkenylene, or C₂₋₆ alkylylene moiety; R¹ is C₁₋₆ alkyl, C₂₋₆alkenyl, C₁₋₆ haloalkyl, C₃₋₁₂ cycloalkyl, heterocyclyl, aryl,arylC₁₋₆alkyl, heteroaryl, or heteroarylC₁₋₆ alkyl, wherein the alkyl,aryl, arylalkyl, heteroaryl, and heteroarylalkyl are optionallysubstituted with one, two, three, or four groups that are eachindependently halogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —OR⁷,—SR⁷, —N(R⁷)₂, —C(O)R⁷, —C(O)OR⁷, —C(O)N(R⁷)₂, —S(O)₂R⁷, —OC(O)R⁷,—OC(O)OR⁷, —OC(O)N(R⁷)₂, —N(R⁷)C(O)R⁷, —N(R⁷)C(O)OR⁷, or—N(R⁷)C(O)N(R⁷)₂, wherein each R⁷ is independently hydrogen or C₁₋₆alkyl; R² is hydrogen, halogen, C₁₋₆ alkyl, or —OR⁸, where R⁸ isselected from the group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₂ cycloalkyl, heterocyclyl, aryl, arylC₁₋₆alkyl, heteroaryl, or heteroaryIC₁₋₆ alkyl, wherein the alkyl, aryl,arylalkyl, heteroaryl, and heteroarylalkyl are optionally substitutedwith one, two, three, or four groups that are each independentlyhalogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —OR⁷, —SR⁷, —N(R⁷)₂,—C(O)R⁷, —C(O)OR⁷, —C(O)N(R⁷)₂, —S(O)₂R⁷, —OC(O)R⁷, —OC(O)OR⁷,—OC(O)N(R⁷)₂, —N(R⁷)C(O)R⁷, —N(R⁷)C(O)OR⁷, or —N(R⁷)C(O)N(R⁷)₂, whereineach R⁷ is independently hydrogen or C₁₋₆ alkyl; or R¹ and R² togetherwith the atoms to which they are attached form a C₃₋₁₂ cycloalkyl,heterocyclyl, aryl, or heteroaryl, each optionally substituted with one,two, three, or four groups that are each independently halogen, cyano,nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —OR⁷, —SR⁷, —N(R⁷)₂, —C(O)R⁷,—C(O)OR⁷, —C(O)N(R⁷)₂, —S(O)₂R⁷, —OC(O)R⁷, —OC(O)OR⁷, —OC(O)N(R⁷)₂,—N(R⁷)C(O)R⁷, —N(R⁷)C(O)OR⁷, or —N(R⁷)C(O)N(R⁷)₂; and R³ is hydrogen,C₁₋₆ alkyl, C₁₋₆ haloalkyl, —OR, —SR, or —NR₂, and each R isindependently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ haloalkyl, C₃₋₁₂cycloalkyl, heterocyclyl, aryl, arylC₁₋₆ alkyl, heteroaryl, orheteroarylC₁₋₆alkyl, wherein the alkyl, aryl, arylalkyl, heteroaryl, andheteroarylalkyl are optionally substituted with one, two, three, or fourgroups that are each independently halogen, cyano, nitro, C₁₋₆ alkyl,C₁₋₆ haloalkyl, —OR⁰, —SR⁰, —N(R⁰)₂, —C(O)R⁰, —C(O)OR⁰, —C(O)N(R⁰)₂,—S(O)₂R⁰, —OC(O)R⁰, —OC(O)OR⁰, —OC(O)N(R⁰)₂, —N(R⁰)C(O)R⁰,—N(R⁰)C(O)OR⁰, or —N(R⁰)C(O)N(R⁰)₂, wherein each R⁰ is independentlyhydrogen or C₁₋₆ alkyl.
 2. A compound according to claim 1, wherein A isoptionally substituted phenyl having the formula:


3. A compound according to claim 1, wherein A is optionally substitutednaphthyl having the formula:


4. A compound according to any one of claims 1-3, wherein X is —CH₂—,—CHR⁵—, —NR⁴—, —O—, —S—, —SO—, —SO₂—, —C(O)—, —C(NR⁴)—, or X is offormula

wherein each n is independently 1, 2, or 3; each R⁴ is independentlyhydrogen or C₁₋₆ alkyl; and R⁵ is independently hydrogen, C₁₋₆ alkyl, or—OR⁶, where R⁶ is selected from the group consisting of hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₂ cycloalkyl, heterocyclyl, aryl,arylC₁₋₆ alkyl, heteroaryl, or heteroarylC₁₋₆alkyl.
 5. A compoundaccording to claim 4, wherein X is —CH₂—, —CHR⁵—, —NR⁴—, —O—, —S—, —SO—,—SO₂—, —C(O)—, —C(NR⁴)—, wherein each R⁴ is independently hydrogen orC₁₋₆ alkyl; and R⁵ is independently hydrogen, C₁₋₆ alkyl, or —OR⁶, whereR⁶ is selected from the group consisting of hydrogen, C₁₋₅ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₂ cycloalkyl, heterocyclyl, aryl,arylC₁₋₆alkyl, heteroaryl, or heteroarylC₁₋₆alkyl.
 6. A compoundaccording to claim 4, wherein X is —CH₂— or —CHR⁵—, wherein R⁵ isindependently hydrogen, C₁₋₆ alkyl, or —OR⁶, where R⁶ is selected fromthe group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₂ cycloalkyl, heterocyclyl, aryl, arylC₁₋₆ alkyl,heteroaryl, or heteroarylC₁₋₆alkyl.
 7. A compound according to claim 6,wherein X is —CH₂—.
 8. A compound according to claim 4, wherein X is—NR⁴ ₂—, —O—, —S—, —SO—, —SO₂—, —C(O)—, —C(NR⁴)—, wherein each R⁴ isindependently hydrogen or C₁₋₆ alkyl.
 9. A compound according to claim8, wherein X is —O—, —S—, —SO—, —SO₂—, —C(O)—, or —C(NR⁴)—.
 10. Acompound according to claim 8, wherein X is —O—, —S—, —SO—, or —SO₂—.11. A compound according to claim 8, wherein X is —O—.
 12. A compoundaccording to claim 8, wherein X is —S—, —SO—, or —SO₂—.
 13. A compoundaccording to claim 8, wherein X is —C(O)—.
 14. A compound according toclaim 4, wherein X is of formula

and each n is independently 1 or
 2. 15. A compound according to claim14, wherein each n is independently
 1. 16. A compound according to anyone of claims 1-3 wherein X is a bond.
 17. A compound according to anyone of claims 1-3, wherein X is a bond, —CH₂—, —NH—, —S—, —SO₂, —C(O)—,


18. A compound according to any one of claims 1-3, wherein X is —CH₂—,—NH—, —S—, —SO₂—, —C(O)—,


19. A compound according to any one of claims 1-18, wherein Y is C₁₋₆alkylene or C₂₋₆ alkenylene.
 20. A compound according to claim 19,wherein Y is C₁₋₄ alkylene or C₂₋₄ alkenylene.
 21. A compound accordingto claim 19, wherein Y is C₁₋₄ alkylene.
 22. A compound according toclaim 21, wherein Y is methylene, ethylene, or propylene.
 23. A compoundaccording to claim 22, wherein Y is methylene or ethylene.
 24. Acompound according to claim 19, wherein Y is C₂₋₄ alkenylene.
 25. Acompound according to claim 24, wherein Y is —CH═CH—, —CH₂CH═CH—, or—CH═CHCH₂—.
 26. A compound according to any one of claims 1-18, whereinY is methylene, ethylene, or —CH═CH—.
 27. A compound according to anyone of claims 1-26, wherein R³ is hydrogen, C₁₋₆ alkyl, —OR, or —NR₂,and each R is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆haloalkyl, C₃₋₁₂ cycloalkyl, heterocyclyl, aryl, arylC₁₋₆ alkyl,heteroaryl, or heteroarylC₁₋₆alkyl, wherein the alkyl, aryl, arylalkyl,heteroaryl, and heteroarylalkyl are optionally substituted with one,two, three, or four groups that are each independently halogen, cyano,nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —OR⁶, —SR⁰, —N(R⁰)₂, —C(O)R⁰,—C(O)OR⁰, —C(O)N(R⁰)₂, —S(O)₂R⁰, —OC(O)R⁰, —OC(O)OR⁰, —OC(O)N(R⁰)₂,—N(R⁰)C(O)R⁰, —N(R⁰)C(O)OR⁰, or —N(R⁰)C(O)N(R⁰)₂, wherein each R⁰ isindependently hydrogen or C₁₋₆ alkyl.
 28. A compound according to claim27, wherein R³ is hydrogen or C₁₋₆ alkyl.
 29. A compound according toclaim 28, wherein R³ is hydrogen.
 30. A compound according to claim 28,wherein R³ is C₁₋₆ alkyl.
 31. A compound according to claim 27, whereinR³ is —NR₂.
 32. A compound according to claim 31, wherein each R isindependently hydrogen or C₁₋₆ alkyl optionally substituted with one,two, three, or four groups that are each independently halogen, cyano,nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —OR⁰, —SR⁰, —N(R⁰)₂, —C(O)R⁰,—C(O)OR⁰, —C(O)N(R⁰)₂, —S(O)₂R⁰, —OC(O)R⁰, —OC(O)OR⁰, —OC(O)N(R⁰)₂,—N(R⁰)C(O)R⁰, 'N(R⁰)C(O)OR⁰, or —N(R⁰)C(O)N(R⁰)₂, wherein each R⁰ isindependently hydrogen or C₁₋₆ alkyl.
 33. A compound according to claim27, wherein R³ is —OR.
 34. A compound according to claim 33, wherein Ris hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ haloalkyl, C₃₋₁₂ cycloalkyl,heterocyclyl, aryl, arylC₁₋₆ alkyl, heteroaryl, or heteroarylC₁₋₆ alkyl,wherein the alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl areoptionally substituted with one, two, three, or four groups that areeach independently halogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl,—OR⁰, —SR⁰, —N(R⁰)₂, —C(O)R⁰, —C(O)OR⁰, —C(O)N(R⁰)₂, and —S(O)₂R⁰,wherein each R⁰ is independently hydrogen or C₁₋₆ alkyl.
 35. A compoundaccording to claim 33, wherein R is hydrogen, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₁₂ cycloalkyl, aryl, arylC₁₋₆ alkyl, heteroaryl, orheteroarylC₁₋₆ alkyl, wherein the alkyl, aryl, arylalkyl, heteroaryl,and heteroarylalkyl are optionally substituted with one, two, three, orfour groups that are each independently halogen, cyano, nitro, C₁₋₆alkyl, C₁₋₆ haloalkyl, —OR⁰, —SR⁰, —N(R⁰)₂, —C(O)R⁰, —C(O)OR⁰,—C(O)N(R⁰)₂, and —S(O)₂R⁰, wherein each R⁰ is independently hydrogen orC₁₋₆ alkyl.
 36. A compound according to claim 33, wherein R is hydrogen,C₁₋₆ alkyl, C₁₋₆ haloalkyl, or arylC₁₋₆ alkyl, wherein the alkyl andarylalkyl are optionally substituted with one, two, three, or fourgroups that are each independently halogen, cyano, nitro, C₁₋₆ alkyl,C₁₋₆ haloalkyl, —OR⁰, —S⁰, —N(R⁰)₂, —C(O)R⁰, —C(O)OR⁰, —C(O)N(R⁰)₂, and—S(O)₂R⁰, wherein each R⁰ is independently hydrogen or C₁₋₆ alkyl.
 37. Acompound according to claim 33, wherein R is hydrogen or C₁₋₆ alkyl. 38.A compound according to claim 37, wherein R is hydrogen.
 39. A compoundaccording to claim 37, wherein R is C₁₋₄ alkyl.
 40. A compound accordingto claim 37, wherein R is hydrogen, methyl, ethyl, propyl, or butyl. 41.A compound according to claim 33, wherein R is arylC₁₋₆ alkyl.
 42. Acompound according to claim 41, wherein R is benzyl.
 43. A compoundaccording to any one of claims 1-42, wherein R¹ and R² together with theatoms to which they are attached form a C₃₋₁₂ cycloalkyl, heterocyclyl,aryl, or heteroaryl, each optionally substituted with one, two, three,or four groups that are each independently halogen, cyano, nitro, C₁₋₆alkyl, C₁₋₆ haloalkyl, —OR⁷, —SR⁷, —N(R⁷)₂, —C(O)R⁷, —C(O)OR⁷,—C(O)N(R⁷)₂, —S(O)₂R⁷, —OC(O)R⁷, —OC(O)OR⁷, —OC(O)N(R⁷)₂, —N(R⁷) C(O)R⁷,—N(R⁷)C(O)OR⁷, or —N(R⁷)C(O)N(R⁷)₂.
 44. A compound according to claim43, wherein R¹ and R² together with the atoms to which they are attachedform a C₃₋₁₂ cycloalkyl, optionally substituted with one, two, three, orfour groups that are each independently halogen, cyano, nitro, C₁₋₆alkyl, C₁₋₆ haloalkyl, —OR⁷, —SR⁷, —N(R⁷)₂, —C(O)R⁷, —C(O)OR⁷,—C(O)N(R⁷)₂, —S(O)₂R⁷, —OC(O)R⁷, —OC(O)OR⁷, —OC(O)N(R⁷)₂, —N(R⁷)C(O)R⁷,—N(R⁷)C(O)OR⁷, or —N(R⁷)C(O)N(R⁷)₂.
 45. A compound according to claim44, wherein R¹ and R² together with the atoms to which they are attachedform a cyclohexane, optionally substituted with one, two, three, or fourgroups that are each independently halogen, cyano, nitro, C₁₋₆ alkyl,C₁₋₆ haloalkyl, —OR⁷, —SR⁷, —N(R⁷)₂, —C(O)R⁷, —C(O)OR⁷, —C(O)N(R⁷)₂,—S(O)₂R⁷, —OC(O)R⁷, —OC(O)OR⁷, —OC(O)N(R⁷)₂, —N(R⁷)C(O)R⁷,—N(R⁷)C(O)OR⁷, or —N(R⁷)C(O)N(R⁷)₂.
 46. A compound according to claim44, wherein R¹ and R² together with the atoms to which they are attachedform a cyclohexane substituted with four C₁₋₆ alkyl groups.
 47. Acompound according to claim 46, wherein R¹ and R² together with theatoms to which they are attached form:


48. A compound according to any one of claims 1-42, wherein R¹ is C₁₋₆alkyl, C₁₋₆ alkenyl, C₁₋₆ haloalkyl, C₃₋₁₂ cycloalkyl, heterocyclyl,aryl, arylC₁₋₆ alkyl, heteroaryl, or heteroarylC₁₋₆ alkyl, wherein thealkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl are optionallysubstituted with one, two, three, or four groups that are eachindependently halogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —OR⁷,—SR⁷, —N(R⁷)₂, —C(O)R⁷, —C(O)OR⁷, —C(O)N(R⁷)₂, —S(O)₂R⁷, —OC(O)R⁷,—OC(O)OR⁷, —OC(O)N(R⁷)₂, —N(R⁷)C(O)R⁷, —N(R⁷)C(O)OR⁷, or—N(R⁷)C(O)N(R⁷)₂, wherein each R⁷ is independently hydrogen or C₁₋₆alkyl; and R² is hydrogen, halogen, C₁₋₆ alkyl, or —OR⁸, where R⁸ isselected from the group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₂ cycloalkyl, heterocyclyl, aryl, arylC₁₋₆alkyl, heteroaryl, or heteroarylC₁₋₆ alkyl, wherein the alkyl, aryl,arylalkyl, heteroaryl, and heteroarylalkyl are optionally substitutedwith one, two, three, or four groups that are each independentlyhalogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —OR⁷, —SR⁷, —N(R⁷)₂,—C(O)R⁷, —C(O)OR⁷, —C(O)N(R⁷)₂, —S(O)₂R⁷, —OC(O)R⁷, —OC(O)OR⁷,—OC(O)N(R⁷)₂, —N(R⁷)C(O)R⁷, —N(R⁷)C(O)OR⁷, or —N(R⁷)C(O)N(R⁷)₂, whereineach R⁷ is independently hydrogen or C₁₋₆ alkyl.
 49. A compoundaccording to any one of claims 1-42 and 48, wherein R¹ is C₁₋₆ alkyl,C₃₋₁₂ cycloalkyl, heterocyclyl, aryl, arylC₁₋₆ alkyl, heteroaryl, orheteroarylC₁₋₆alkyl, wherein the alkyl, aryl, arylalkyl, heteroaryl, andheteroarylalkyl are optionally substituted with one, two, three, or fourgroups that are each independently halogen, cyano, nitro, C₁₋₆ alkyl,C₁₋₆ haloalkyl, —OR⁷, —SR⁷, —N(R⁷)₂, —C(O)R⁷, —C(O)OR⁷, —C(O)N(R⁷)₂,—S(O)₂R⁷, —OC(O)R⁷, —OC(O)OR⁷, —OC(O)N(R⁷)₂, —N(R⁷)C(O)R⁷,—N(R⁷)C(O)OR⁷, or —N(R⁷)C(O)N(R⁷)₂, wherein each R⁷ is independentlyhydrogen or C₁₋₆ alkyl.
 50. A compound according to claim 49, wherein R¹is C₁₋₆ alkyl, C₃₋₁₂ cycloalkyl, or arylC₁₋₆ alkyl, wherein the alkyland arylalkyl, heteroaryl are optionally substituted with one, two,three, or four groups that are each independently halogen, cyano, nitro,C₁₋₆ alkyl, C₁₋₆ haloalkyl, —OR⁷, —SR⁷, —N(R⁷)₂, —C(O)R⁷, —C(O)OR⁷,—C(O)N(R⁷)₂, —S(O)₂R⁷, —OC(O)R⁷, —OC(O)OR⁷, —OC(O)N(R⁷)₂, —N(R⁷)C(O)R⁷,—N(R⁷)C(O)OR⁷, or —N(R⁷)C(O)N(R⁷)₂, wherein each R⁷ is independentlyhydrogen or C₁₋₆ alkyl.
 51. A compound according to claim 49, wherein R¹is C₁₋₆ alkyl or C₃₋₁₂ cycloalkyl, each optionally substituted with one,two, three, or four groups that are each independently halogen, cyano,nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —OR⁷, —SR⁷, —N(R⁷)₂, —C(O)R⁷,—C(O)OR⁷, —C(O)N(R⁷)₂, —S(O)₂R⁷, —OC(O)R⁷, —OC(O)OR⁷, —OC(O)N(R⁷)₂,—N(R⁷)C(O)R⁷, —N(R⁷)C(O)OR⁷, or —N(R⁷)C(O)N(R⁷)₂, wherein each R⁷ isindependently hydrogen or C₁₋₆ alkyl.
 52. A compound according to claim49, wherein R¹ is optionally substituted C₁₋₆ alkyl.
 53. A compoundaccording to claim 52, wherein R¹ is unsubstituted C₁₋₆ alkyl.
 54. Acompound according to claim 53, wherein R¹ is tert-butyl.
 55. A compoundaccording to claim 49, wherein R¹ is optionally substituted C₃₋₁₂cycloalkyl.
 56. A compound according to claim 55, wherein R¹ isunsubstituted C₃₋₁₂ cycloalkyl.
 57. A compound according to claim 54,wherein R¹ is adamantyl.
 58. A compound according to any one of claims1-42 and 48-57, wherein R² is halogen, C₁₋₆ alkyl, or —OR⁸.
 59. Acompound according to claim 58, wherein R² is halogen or C₁₋₆ alkyl. 60.A compound according to claim 58, wherein R² is —OR⁸.
 61. A compoundaccording to claim 60, wherein R⁸ is selected from the group consistingof hydrogen, C₁₋₆ alkyl, C₃₋₁₂ cycloalkyl, heterocyclyl, aryl, arylC₁₋₆alkyl, heteroaryl, or heteroarylC₁₋₆ alkyl, wherein the alkyl, aryl,arylalkyl, heteroaryl, and heteroarylalkyl are optionally substitutedwith one, two, three, or four groups that are each independentlyhalogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —OR⁷, —SR⁷, —N(R⁷)₂,—C(O)R⁷, —C(O)OR⁷, —C(O)N(R⁷)₂, —S(O)₂R⁷, —OC(O)R⁷, —OC(O)OR⁷,—OC(O)N(R⁷)₂, —N(R⁷) C(O)R⁷, —N(R⁷)C(O)OR⁷, or —N(R⁷)C(ONR⁷)₂, whereineach R⁷ is independently hydrogen or C₁₋₆ alkyl.
 62. A compoundaccording to claim 60, wherein R⁸ is selected from the group consistingof hydrogen, C₁₋₆ alkyl, or arylC₁₋₆ alkyl, wherein the alkyl andarylalkyl are optionally substituted with one, two, three, or fourgroups that are each independently halogen, cyano, nitro, C₁₋₆ alkyl,C₁₋₆ haloalkyl, —OR⁷, —SR⁷, —N(R⁷)₂, —C(O)R⁷, —C(O)OR⁷, —C(O)N(R⁷)₂,—S(O)₂R⁷, —OC(O)R⁷, —OC(O)OR⁷, —OC(O)N(R⁷)₂, —N(R⁷)C(O)R⁷,—N(R⁷)C(O)OR⁷, or —N(R⁷)C(O)N(R⁷)₂, wherein each R⁷ is independentlyhydrogen or C₁₋₆ alkyl.
 63. A compound according to claim 60, wherein R⁸is of hydrogen or C₁₋₆ alkyl.
 64. A compound according to claim 60,wherein R⁸ is of hydrogen.
 65. A compound according to claim 60, whereinR⁸ is C₁₋₆ alkyl.
 66. A compound according to claim 60, wherein R⁸ is ofhydrogen or methyl.
 67. A compound according to claim 60, wherein R⁸ isof arylC₁₋₆alkyl.
 68. A compound according to claim 60, wherein R⁸ isbenzyl.
 69. A compound according to claim 60, wherein R⁸ is of hydrogen,C₁₋₆ alkyl, or benzyl.
 70. A compound according to claim 1, which is:Methyl 2-(4-{[3-(adamantan-1-yl)-4-methoxyphenyl]sulfanyl}phenyl)acetateButyl 2-(4-{[3-(adamantan-1-yl)-4-methoxyphenyl]sulfanyl}phenyl)acetate2-(4-{[3-(adamantan-1-yl)-4-methoxyphenyl]sulfanyl}phenyl)acetic acidMethyl2-(3-{[3-(adamantan-1-yl)-4-methoxyphenyl]sulfanyl}phenyl)acetate; Butyl2-(3-{[3-(adamantan-1-yl)-4-methoxyphenyl]sulfanyl}phenyl)acetate2-(3-{[3-(Adamantan-1-yl)-4-methoxyphenyl]sulfanyl}phenyl)acetic acidMethyl2-{4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)sulfanyl]phenyl}acetateButyl2-{4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)sulfanyl]phenyl}acetate2-{4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)sulfanyl]phenyl}aceticacid Methyl2-{3-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)sulfanyl]phenyl}acetateButyl2-{3-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)sulfanyl]phenyl}acetate2-{3-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)sulfanyl]phenyl}aceticacid Methyl2-(4-{[3-(adamantan-1-yl)-4-methoxybenzene]sulfonyl}phenyl)acetate Butyl2-(4-{[3-(adamantan-1-yl)-4-methoxybenzene]sulfonyl}phenyl)acetate2-(4-{[3-(adamantan-1-yl)-4-methoxybenzene]sulfonyl}phenyl)acetic acidMethyl2-(3-{[3-(adamantan-1-yl)-4-methoxybenzene]sulfonyl}phenyl)acetate Butyl2-(3-{[3-(adamantan-1-yl)-4-methoxybenzene]sulfonyl}phenyl)acetate2-(3-{[3-(adamantan-1-yl)-4-methoxybenzene]sulfonyl}phenyl)acetic acidMethyl2-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-sulfonyl)phenyl]acetateButyl2-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-sulfonyl)phenyl]acetate2-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-sulfonyl)phenyl]aceticacid Methyl2-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-sulfonyl)phenyl]acetate2-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-sulfonyl)phenyl]aceticacid Ethyl3-{4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)sulfanyl]phenyl}propanoateEthyl3-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-sulfonyl)phenyl]propanoate3-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-sulfonyl)phenyl]propanoicacid Ethyl3-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)phenyl]propanoate3-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)phenyl]propanoicacid Ethyl 3-{4-[3-(adamantan-1-yl)-4-methoxyphenyl]phenyl}propanoate3-{4-[3-(adamantan-1-yl)-4-methoxyphenyl]phenyl}propanoic acid3-{4-[3-(adamantan-1-yl)-4-hydroxyphenyl]phenyl}propanoic acid Benzyl(2E)-3-{4-[3-(adamantan-1-yl)-4-methoxyphenyl]phenyl}prop-2-enoate2(E)-3-{4-[3-(adamantan-1-yl)-4-methoxyphenyl]phenyl}prop-2-enoic acid;(2E)-3-{4-[3-(adamantan-1-yl)-4-hydroxyphenyl]phenyl}prop-2-enoic acid;Benzyl(2E)-3-(4-{[3-(adamantan-1-yl)-4-methoxyphenyl]amino}phenyl)prop-2-enoate(2E)-3-(4-{[3-(adamantan-1-yl)-4-methoxyphenyl]amino}phenyl)prop-2-enoicacid;(2E)-3-(4-{[3-(adamantan-1-yl)-4-hydroxyphenyl]amino}phenyl)prop-2-enoicacid; 3-(4-{[3-(adamantan-1-yl)-4-hydroxyphenyl]amino}phenyl)propanoicacid 3-(4-{[3-(adamantan-1-yl)-4-hydroxyphenyl]amino}phenyl)propanoicacid; Benzyl(2E)-3-{4-[(3-tert-butyl-4-methoxyphenyl)amino]phenyl}prop-2-enoate;3-{4-[(3-tert-butyl-4-methoxyphenyl)amino]phenyl}propanoic acid Methyl(2E)-3-{4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dioxolan-2-yl]phenyl}prop-2-enoate;3-{4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dioxolan-2-yl]phenyl}propanoicacid Methyl3-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-carbonyl)phenyl]propanoate;3-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-carbonyl)phenyl]propanoicacid Methyl(2E)-3-{4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]phenyl}prop-2-enoate;Methyl(2E)-3-{4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dithiolan-2-yl]phenyl}prop-2-enoate;(2E)-3-{4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dithiolan-2-yl]phenyl}prop-2-enoicacid;(2E)-3-{4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]phenyl}prop-2-enoicacid; Methyl3-{4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dithiolan-2-yl]phenyl}propanoate;3-{4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dithiolan-2-yl]phenyl}propanoicacid; Methyl3-{4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methyl]phenyl}propanoate;3-{4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methyl]phenyl}propanoicacid; Benzyl(2E)-3-{4-[(3-tert-butyl-4-methoxyphenyl)carbonyl]phenyl}prop-2-enoate;3-{4-[(3-tert-butyl-4-methoxyphenyl)methyl]phenyl}propanoic acid; Methyl(2E)-3-{4-[(3-tert-butyl-4-methoxyphenyl)carbonyl]phenyl}prop-2-enoate;(2E)-3-{4-[(3-tert-butyl-4-methoxyphenyl)carbonyl]phenyl}prop-2-enoicacid; Methyl(2E)-3-{4-[2-(3-tert-butyl-4-methoxyphenyl)-1,3-dioxolan-2-yl]phenyl}prop-2-enoate;Methyl3-{4-[2-(3-tert-butyl-4-methoxyphenyl)-1,3-dioxolan-2-yl]phenyl}propanoate3-{4-[2-(3-tert-butyl-4-methoxyphenyl)-1,3-dioxolan-2-yl]phenyl}propanoicacid; Benzyl 3-[4-(5-tert-butyl-2-methoxybenzoyl)phenyl]propanoate3-{4-[(5-tert-butyl-2-methoxyphenyl)methyl]phenyl}propanoic acid; Benzyl(2E)-3-[4(5-tert-butyl-2-hydroxybenzoyl)phenyl]prop-2-enoate;3-{4-[(5-tert-butyl-2-hydroxyphenyl)methyl]phenyl}propanoic acid; Benzyl(2E)-3-{4-[2-(5-tert-butyl-2-methoxyphenyl)-1,3-dioxolan-2-yl]phenyl}prop-2-enoate;Methyl 3-{4-[(5-tert-butyl-2-methoxyphenyl)carbonyl]phenyl}propanoate;3-{4-[(5-tert-butyl-2-methoxyphenyl)carbonyl]phenyl}propanoic acid;methyl(2E)-3-{4-[5-(adamantan-1-yl)-2-methoxybenzoyl]phenyl}prop-2-enoate;Methyl(2E)-3-(4-{2-[5-(adamantan-1-yl)-2-methoxyphenyl]-1,3-dioxolan-2-yl}phenyl)prop-2-enoate;(2E)-3-(4-{2-[5-(adamantan-1-yl)-2-methoxyphenyl]-1,3-dioxolan-2-yl}phenyl)prop-2-enoicacid;3-(4-{2-[5-(adamantan-1-yl)-2-methoxyphenyl]-1,3-dioxolan-2-yl}phenyl)propanoicacid; Methyl3-(4-{2-[5-(adamantan-1-yl)-2-methoxyphenyl]-1,3-dioxolan-2-yl}phenyl)propanoate;Methyl 3-{4-[5-(adamantan-1-yl)-2-methoxybenzoyl]phenyl}propanoate;Methyl3-(4-{2-[5-(adamantan-1-yl)-2-methoxyphenyl]-1,3-dithiolan-2-yl}phenyl)propanoate;3-(4-{2-[5-(adamantan-1-yl)-2-methoxyphenyl]-1,3-dithiolan-2-yl}phenyl)propanoicacid; Methyl(2E)-3-{4-[5-(adamantan-1-yl)-2-hydroxybenzoyl]phenyl}prop-2-enoate;Methyl3-(4-{[5-(adamantan-1-yl)-2-hydroxyphenyl]methyl}phenyl)propanoate;3-(4-{[5-(adamantan-1-yl)-2-hydroxyphenyl]methyl}phenyl)propanoic acid;or pharmaceutically acceptable salts thereof
 71. A pharmaceuticalcomposition comprising one or more of compounds according to any one ofclaims 1-70 and a pharmaceutically acceptable carrier, diluent, orexcipient.
 72. A method for treating diseases that are ameliorated bythe inhibition of CYP26 mediated retinoic acid metabolism comprisingproviding to a patient in need of such treatment a therapeuticallyeffective amount of either a compound according to any one of claims1-70 or a pharmaceutical composition of claim
 71. 73. The method ofclaim 72, wherein the disease is selected from the group consisting ofcancer, neurodegenerative disease, and a dermatological disorder. 74.The method of claim 73, wherein the disease is cancer, and the cancer isselected from the group consisting of acute promyelocytic leukaemia,neuroblastoma, basal cell and squamous cell carcinomas, prostate cancer,lung cancer, and breast cancer.
 75. The method of claim 73, wherein thedisease is neurodegenerative disease, and the neurodegenerative diseaseis selected from the group consisting of Alzheimer's disease,Parkinson's disease, and stroke.
 76. The method of claim 73, wherein thedisease is a dermatological disorder, and the dermatological disorder isselected from the group consisting of acne, psoriasis, and ichthyosis.77. A method for treating diseases that are ameliorated by theinhibition CYP26 mediated retinoic acid metabolism comprising providingto a patient in need of such treatment a therapeutically effectiveamount of a compound of formula (II) or a pharmaceutical compositioncomprising one or more of compounds of formula (II) and apharmaceutically acceptable carrier, diluent, or excipient, whereinformula (II) is:

or a pharmaceutically acceptable salt thereof, wherein A represents aryloptionally substituted with one, two, three, or four groups that areeach independently halogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl,—NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —OH, C₁-C₆ alkoxy, and C₁-C₆haloalkoxy; X is a bond, —CH₂—, —CHR⁵, —C═CHR⁴—, —NR⁴—, —N═O—R⁴—, —O—,—S—, —SO—, —SO₂—, —C(O)—, —C(S)—, —C(CH₂)—, —C(NR⁴)—, —C(O)CH₂O—,—CH(OR⁴)CH₂O—, —C(NR⁴)CH₂O—, or —CH(N(R⁴)₂)CH₂O—, or X is of formula

wherein each n is independently 1, 2, or 3; each R⁴ is independentlyhydrogen or C₁₋₆ alkyl; R⁵ is independently hydrogen, C₁₋₆ alkyl, or—OR⁶, where R⁶ is selected from the group consisting of hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₂ cycloalkyl, heterocyclyl, aryl,arylC₁₋₆ alkyl, heteroaryl, or heteroarylC₁₋₆ alkyl; Y is C₁₋₆ alkylene,C₂₋₆ alkenylene, or C₂₋₆ alkylylene moiety; R¹ is C₁₋₆ alkyl, C₂₋₆alkenyl, C₁₋₆ haloalkyl, C₃₋₁₂ cycloalkyl, heterocyclyl, aryl, arylC₁₋₆alkyl, heteroaryl, or heteroarylC₁₋₆ alkyl, wherein the alkyl, aryl,arylalkyl, heteroalyl, and heteroarylalkyl are optionally substitutedwith one, two, three, or four groups that are each independentlyhalogen, cyano, nitro, C₁₋₆ alkyl, C₁₋₆ haloalkyl, —OR⁷, —SR⁷, —N(R⁷)₂,—C(O)R⁷, —C(O)OR⁷, —C(O)N(R⁷)₂, —S(O)₂R⁷, —OC(O)R⁷, —OC(O)OR⁷,—OC(O)N(R⁷)₂, —N(R⁷)C(O)R⁷, —N(R⁷)C(O)OR⁷, or —N(R⁷)C(O)N(R⁷)₂, whereineach R⁷ is independently hydrogen or C₁₋₆ alkyl; R² is hydrogen,halogen, C₁₋₆ alkyl, or —OR⁶, where R⁸ is selected from the groupconsisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₂cycloalkyl, heterocyclyl, aryl, arylC₁₋₆ alkyl, heteroaryl, orheteroarylC₁₋₆ alkyl, wherein the alkyl, aryl, arylalkyl, heteroaryl,and heteroarylalkyl are optionally substituted with one, two, three, orfour groups that are each independently halogen, cyano, nitro, C₁₋₆alkyl, C₁₋₆ haloalkyl, —OR⁷, —SR⁷, —N(R⁷)₂, —C(O)R⁷, —C(O)OR⁷,—C(O)N(R⁷)₂, —S(O)₂R⁷, —OC(O)R⁷, —OC(O)OR⁷, —OC(O)N(R⁷)₂, —N(R⁷)C(O)R⁷,—N(R⁷)C(O)OR⁷, or —N(R⁷)C(O)N(R⁷)₂, wherein each R⁷ is independentlyhydrogen or C₁₋₆ alkyl; or R¹ and R² together with the atoms to whichthey are attached form a C₃₋₁₂ cycloalkyl, heterocyclyl, aryl, orheteroaryl, each optionally substituted with one, two, three, or fourgroups that are each independently halogen, cyano, nitro, C₁₋₆ alkyl,C₁₋₆ haloalkyl, —OR⁷, —SR⁷, —N(R⁷)₂, —C(O)R⁷, —C(O)OR⁷, —C(O)N(R⁷)₂,—S(O)₂R⁷, —OC(O)R⁷, —OC(O)OR⁷, —OC(O)N(R⁷)₂, —N(R⁷)C(O)R⁷,—N(R⁷)C(O)OR⁷, or —N(R⁷)C(O)N(R⁷)₂; and R³ is hydrogen, C₁₋₆ alkyl, C₁₋₆haloalkyl, —OR, —SR, or —NR₂, and each R is independently hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₁₋₆ haloalkyl, C₃₋₁₂ cycloalkyl, heterocyclyl,aryl, arylC₁₋₆alkyl, heteroaryl, or heteroarylC₁₋₆ alkyl, wherein thealkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl are optionallysubstituted with one, two, three, or four groups that are eachindependently halogen, cyano, nitro, C₁₋₆ alkyl , C₁₋₆ haloalkyl, —OR⁰,—SR⁰, —N(R⁰)₂, —C(O)R⁰, —C(O)OR⁰, —C(O)N(R⁰)₂, —S(O)₂R⁰, —OC(O)R⁰,—OC(O)OR⁰, —OC(O)N(R⁰)₂, —N(R⁰)C(O)R⁰, —N(R⁰C(O)OR⁰, or—N(R⁰)C(O)N(R⁰)₂, wherein each R⁰ is independently hydrogen or C₁₋₆alkyl.
 78. The method of claim 77, wherein the disease is selected fromthe group consisting of cancer, neurodegenerative disease, anddermatological disorder.
 79. The method of claim 78, wherein the diseaseis cancer, and the cancer is selected from the group consisting of acutepromyelocytic leukaemia, neuroblastoma, basal cell and squamous cellcarcinomas, prostate cancer, lung cancer, and breast cancer.
 80. Themethod of claim 78, wherein the disease is neurodegenerative disease,and the neurodegenerative disease is selected from the group consistingof Alzheimer's disease, Parkinson's disease, and stroke.
 81. The methodof claim 78, wherein the disease is a dermatological disorder, and thedermatological disorder is selected from the group consisting of acne,psoriasis, and ichthyosis.